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Natural Products as Sources of New Drugs from 1981 to 2014

Natural Products as Sources of New Drugs from1981to2014 David J.Newman*,?and Gordon M.Cragg?

?NIH Special Volunteer,Wayne,Pennsylvania19087,United States

?NIH Special Volunteer,Bethesda,Maryland20814,United States

*Supporting Information

entities by the U.S.FDA(and similar organizations).From the

and/or their novel structures,in order to discover and develop

of cancer,over the time frame from around the1940s to the

are other than“S”(synthetic),with85,or49%,actually being

areas,the in?uence of natural product structures is quite marked,

being dependent on natural products and their structures.We

recognition that a signi?cant number of natural product drugs/leads

with the“host from whence it was isolated”,and therefore it is

expanded signi?cantly.

It is now18years since the publication of our?rst review

covering drugs from1984to1995;112years since the second,

which covered the period from1981to2002;2eight years since

our third,covering the period1981to the middle of2006;3and

four years4since our last full analysis(covering the period1981

to2010),of the sources of new and approved drugs for the

treatment of human diseases.In the present review we have also

covered the four years from the beginning of2011to the end of

2014.In the last four years we have also published intermediate

reports on natural products as leads to potential drugs,5the

sources of antitumor compounds,6a general discussion on

bioactive macrocycles from Nature,7an e-book series on natural products from microbial sources,8?10and a very recent book chapter on natural products in medicinal chemistry.11All of these articles have emphasized that natural product and/or natural product structures continue to play a highly signi?cant role in the drug discovery and development process.

In Table1,we have shown the genesis of our category codes and the years that we started with them.This is for the bene?t of readers who are not familiar with these de?nitions and their derivation.The detailed reasoning behind the subgroup de?nition is given later under results.

That Nature in one guise or another has continued to in?uence the design of small molecules is shown by inspection of the information given below,where with the advantage of now34years of data from1981to2014the system has been able to be re?ned.We have eliminated some duplicated entries that crept into the original data sets and have continued to revise some source designations,as newer information has been obtained from diverse sources.In particular,as behooves authors originally from the National Cancer Institute(NCI),in the speci?c case of cancer treatments,we have continued to consult the records of the U.S.FDA and have added comments from investigators who

Special Issue:Special Issue in Honor of John Blunt and Murray Munro

Received:November27,2015

Published:February7,2016

Table1.Codes Used in Analyses

code brief de?nition/year

Biological macromolecule,1997

N Unaltered

natural product,1997

NB drug(de?ned mixture),2012

ND Natural product derivative,1997

S Synthetic drug,1997

S*Synthetic drug(NP pharmacophore),1997

V Vaccine,2003

/NM Mimic of natural product,2003

?2016American Chemical Society and

have informed us of compounds that may have been approved in other countries and that were not included in our earlier searches.As was done previously,the cancer data will be presented as a stand-alone section from the beginning of formal chemotherapy in the very late 1930s or early 1940s to the present,but information from the last 34years will be included in the data sets used in the overall discussion.

A trend mentioned in our 2003review,2namely,the development of high-throughput screens based on molecular targets,had led to a demand for the generation of large libraries of compounds;however,the shift away from large combinatorial libraries that was becoming obvious at that time has continued even today,with the emphasis continuing to be on small focused (100?3000plus)collections that contain much of the “structural aspects ”of natural products.As mentioned in our 2012review,4various names have been given to this process,including “diversity oriented syntheses ”,12?16but we prefer to refer simply to “more natural-product-like ”,in terms of their combinations of heteroatoms and signi ?cant numbers of chiral centers within a

single molecule,17or even “natural product mimics ”if they happen to be direct competitive inhibitors of the natural substrate (the origin of our subset listed as “?/NM ”).It should also be pointed out,yet again,that Lipinski ’s ?fth rule e ?ectively states that the ?rst four rules do not apply to natural products nor to any molecule that is recognized by an active transport system when considering “druggable chemical entities ”.18?20An excellent paper by Koehn in 2012gives a listing in Table 1in that article of the 26drugs approved between 1981and 2011based on 18natural product structures that do not obey the “rule of 5”and its strictures.21This paper together with one from Sweden by Doak et al.22and a very recent contribution by Camp et al.23should be part of any discussion on this aspect of natural product drugs.

Commentaries on the “industrial ”perspective in regard to drug sources and high-throughput screening were published by the GSK group 24in 2011,and very recently an intriguing article on what has been called “high throughput screening-dark chemical matter ”(HTS-DCM)has opened the discussion on

Chart

molecules,some of which are based on natural products,that show no activities in in vitro assays but a number of which have very close structural analogues that are active.25,26These papers, the?rst of which is a perspective on the second much larger paper,should also be read in conjunction with a recent paper showing the natural product compound equivalents(invalid metabolic panaceas(IMPS))27to the pan-assay interference compounds(PAINS)that cause major problems in HTS programs.28,29

Although combinatorial chemistry in one or more of its manifestations has now been present as a discovery source for approximately80%of the time covered by this review,to date,we still can only?nd one formal de novo new chemical entity reported in the public domain,with a second possibility discovered in a similar manner,with both approved for drug use.The?rst was the antitumor compound known as sorafenib (Nexavar,1)from Bayer,approved by the FDA in2005for treatment of renal cell carcinoma,and then in2007,another approval was given for treatment of hepatocellular carcinoma.It has been approved in more than100countries as of the middle of 2014for these two indications,and in late2013,the U.S.FDA approved it for treatment of thyroid cancer with further approval for the same indication following in2014in the European Union and Japan.As is customary,it is still in multiple clinical trials in both combination and single-agent therapies.The second drug that probably came about from a de novo sourcing is ataluren (Translarna;2),30which was approved in the EU in2014and launched in Germany the same year for the treatment of patients with genetic disorders due to a“nonsense”mutation.The mechanism of this small molecule can be seen in a diagrammatic mode at the following URL:https://www.wendangku.net/doc/98126884.html,/en/ pipeline/ataluren-translarna/.However,the?rst anticancer drug constructed by use of fragment screening and model?tting, vemurafenib(3),was approved by the FDA in2011,and the story behind this and other small-molecule antitumor agents was well described in a review in2012by Hoelder et al.,which should be consulted for more information on this style of approach to drug discovery.31

As mentioned by the present authors and a signi?cant number of other authors in prior reviews on this topic,the developmental capability of combinatorial chemistry as a means for structural optimization,once an active skeleton has been identi?ed,is without par.An expected surge in productivity,however,did not appear to materialize in the years from2004to2014.Thus,the number of new active substances(NASs)from our data set,also known as new chemical entities(NCEs),which we consider to encompass all molecules,including biologics and vaccines,hit a 24-year low of24in2004(although7,or29%,of these were assigned to the“ND”category),leading to a rebound to52in 2005,with25%being“N”or“ND”and37%being biologics

(“B”)or vaccines(“V”).The next four years from2006to2009 averaged40,with35?45%being vaccines or biologics,although in these four years,four“botanicals”were approved.In2010and 2011,the?gures again dropped to33and34,respectively,but then in2012to2014,the?gures rebounded to60,47,and65, respectively,but biologics and vaccines were signi?cant proportions of these totals.

These?gures are further developed covering the full details by year in Figures2and4(see the Discussion section below), together with other graphs such as Figure5,showing total small molecules/year,Figure6,showing the percentage of natural-product-based compounds and their derivatives.Plus in this review,we have also added the S*series of compounds to these.The use of the S*classi?cation originally arose as a result of doubts expressed by some colleagues working in the chemical synthesis area who questioned the claim that nucleoside analogues synthesized in the laboratory actually evolved from the discoveries by the Bergmann group in the1950s of the arabinose-containing natural products from marine sponges.32?34

The justi?cation for the addition of the“S*”category to natural-product-based compounds and their derivatives in this review is that a large number of the“S*”structures are based on naturally derived nucleosides or very closely related sca?olds,and their relevance to drug discovery will be published in a review in the?rst half of2016.Figure7then shows the percentage of

just Figure1.All new approved drugs1981?2014;n=

1562.

Figure2.All new approved drugs by

source/year.

Figure3.All small-molecule approved drugs1981?2014s;n=1211.

the “N *”categories over the 34years.What is of signi ?cant importance in this area is the very recent paper from the Gerwick group demonstrating the isolation of spongosine (4)from a Vibrio harveyi strain isolated from the same sponge species (Tectitethya crypta )as used by Bergmann 60+years earlier.35However,to allow for comparisons with earlier reviews,we have not altered the categories in the analyses.Fortunately,however,research is still being conducted by (bio)synthetic groups on the modi ?cation of active natural product skeletons as leads to novel agents.This was exempli ?ed recently by publications in 2014?2015from the groups of Szychowski et al.,36Bathula,37Thaker,38

Williams,39Miller,40and Novaes et al.41and an excellent perspective by Nicolaou in 2014.42

Against this backdrop,we now present an updated analysis of the role of natural products in the drug discovery and development process,dating from January 1981through December 2014.As in our earlier analyses,1?4we have consulted the Annual Reports of Medicinal Chemistry ,in this case from 1984to 2014,43?74and to obtain more comprehensive coverage of the 1981?2014time frame we have added data from the publication Drug News and Perspective,75?95the successor listings in Drugs of Today ,96?101and searches of the Prous (now Thomson-Reuter ’s Integrity )database,as well as by including information from individual investigators.As in the last review,the biologics data prior to 2005were updated using information culled from disparate sources that culminated in a 2005review on biopharmaceutical drugs.102We have continued our attempts to capture vaccine data for the past few years,but this area of the database is still not as complete as we would hope.

As in previous reviews in this series,we have continued to include relevant references in a condensed form in Tables 3?6and 9?11.If we had attempted to provide full citations,the numbers of references cited in the present review would become overwhelming.In these tables,“ARMC ##”refers to the volume of Annual Reports in Medicinal Chemistry together with the page on which the structure(s)and commentary can be found.We should point out that due to a change e ?ective in 2015,the ARMC is now known as Medicinal Chemistry Reviews .Similarly,“DNP ##”refers to the volume of Drug News and Perspective and the corresponding page(s),although this journal has now ceased publication as of the 2010volume.Similarly “DT ##”refers to the relevant volume of Drugs of Today and the corresponding page(s),and an “I ######”is the accession number in the Prous (now Thomson-Reuters,Integrity )database.Finally,in the overall listing of antitumor agents from the middle 1930s to 2014(Table 9)we have used “Boyd ”to refer to a review article 103on clinical antitumor agents,an earlier book on the same subject,104and “M ’dale ”to refer to Martindale 105with the relevant page noted.

It must be noted that the “year ”header in all tables is formally equivalent to the “year of introduction ”of the drug in the ?rst country in which it was approved.We only count a drug

once,

Figure 4.All small-molecule approved drugs by

source/year.

Figure 5.Total small

molecules/year.

Figure 6.N,NB,ND,and S *categories by year,1981?2014.

even if subsequently it is approved in other countries or for other indications.Over the years,we have realized that there are discrepancies between sources as to the actual year,often due to di ?erences in de ?nitions between sources.Some reports will use the year of approval (registration by non-USA FDA equivalent organizations),while others will use the ?rst recorded sales.We have generally taken the earliest year in the absence of further information.

■

RESULTS

As in previous reviews,we have,except in a case that will be noted later in this review where a therapy used NCEs (two unapproved agents)in the approved combination,only covered NCEs in the present analysis.As mentioned in earlier reviews,if one reads the U.S.FDA and PhRMA Web sites,the numbers of New Drug Application (NDA)approvals are in the high tens in some of the past few years.The FDA Drugs Database needs to be assessed by anyone using it for drugs previously approved in other countries versus new drugs only approved in the USA to obtain more accurate ?gures,and there will be di ?erences due to our noting drugs approved the ?rst time anywhere and then not counting the same compound the ?rst time it was approved by the https://www.wendangku.net/doc/98126884.html,ing our data (see Figures 2,4,and 5)the number of NCEs has ranged from the 20’s to just over 50per year from 1989to 2011and in 2013for approved NCEs (note that Figures 4and 5count only small molecules),although in 2012and 2014the ?gures reached 60and 65,respectively.The reader needs to bear in mind that our vaccine numbers are not complete,so the overall numbers could increase.If one now removes biologicals and vaccines,thus noting only “small molecules ”(including peptides such as Byetta),then the ?gures show that over the same time frame the numbers have ranged from close to 40for most of the 1989to 2000time frame (except for 2002)to close to 20from 2001to 2010,with the exception of 2002and 2004,when the ?gures climbed above 30.In the last four years (2011to 2014),the numbers have now climbed from 28in 2011to 44(cf.,Figures 2and 4).

Now with 34years of data to analyze,it was decided to add another graph to the listings,together with one of signi ?cant interest to the natural products community.In Figure 6we have plotted a bar graph from 1981to 2014showing the results in numbers/year when the designations used are an “N ”or a subdivision (“NB ”or “ND ”).This time,we have deliberately included the “S *”designation (for the reasons elaborated earlier),which could be considered as “inspired by a natural product structure ”.This ?gure demonstrates that even in 201410of the 44approved small-molecule drugs are “N ”,“NB ”,and

“ND ”with one “S *”,which account for 25%of the 44approved NCEs that year.If we just use the “N ”,“NB ”,and “ND ”designations over the complete 34years,then the mean and standard deviation ?gures in percentages are 33±9,and in Figure 7we have shown the percentage for “N *”values by year.Readers can determine their own ratios for their “year of interest ”,as desired.

As in our earlier reviews,1?4the data have been analyzed in terms of numbers and classi ?ed according to their origin using the previous major categories and their subdivisions.

Major Categories of Sources.The major categories used are as follows:

“B ”:Biological,usually a large (>50residues)peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host

“N ”:Natural product,unmodifed in structure,though might be semi-or totally synthetic

“NB ”:Natural product “botanical drug ”(in general these have been recently approved)

“ND ”:Derived from a natural product and is usually a semisynthetic modi ?cation

“S ”:Totally synthetic drug,often found by random screening/modi ?cation of an existing agent

“S *”:Made by total synthesis,but the pharmacophore is/was from a natural product “V ”:Vaccine

Subcategory.“NM ”:Natural product mimic (see rationale and examples below,as they give the reasoning for the extension of the “S ”and “S *”categories from 2003onward)

In the ?eld of anticancer therapy,the advent in 2001of Gleevec,a protein tyrosine kinase inhibitor,was justly heralded as a breakthrough in the treatment of leukemia.This compound was classi ?ed as an “/NM ”on the basis of its competitive displacement of the natural substrate,ATP,in which the intracellular concentrations can approach 5mM.We have continued to classify most PTK inhibitors that are approved as drugs under the “/NM ”category for exactly the same reasons as elaborated in the 2003review,2although nowadays,some later kinase inhibitors are not competitive inhibitors of ATP and thus would not be classi ?ed this way.The latest discussion on this aspect of PTKs can be read in the 2015paper by Fabbro et al.106(Fabbro can be considered the “developmental father of Gleevec ”),which should be read in conjunction with his 2002paper on PTKs as targets.107In addition,the very interesting recent review by Vijayan et al.108should be consulted,as it demonstrates,together with the 2015paper from Fabbro

Figure 7.Percentage of N *by year,1981?2014.

Table2.New Chemical Entities and Medical Indications by Source of Compound1/1/1981?12/31/2014a indication total B N NB ND S S/NM S*S*/NM V COPD835

analgesic1711132

anesthetic55

anti-Alzheimer61113

anti-Gaucher’s disease5311

anti-Parkinsonian1211514

antiallergic1811412

antianginal55

antiarrhythmic171142

antiarthritic226113461

antiasthmatic1413262

antibacterial1401117129127 anticancer1743317138232013245 anticoagulant2251313

antidepressant278172

antidiabetic,types1and252231641116

antiemetic11128

antiepileptic1721122

antifungal3213253

antiglaucoma145513

antihistamine1414

antihyperprolactinemia44

antihypertensive8022815233

anti-inflammatory5111337

antimigraine10217

antiobesity6114

antiparasitic1625531 antipsoriatic11413111

antipsychotic11362

antithrombotic301315263

antiulcer34111220

antiviral139144145241761 anxiolytic1082

benign prostatic hypertrophy41111

bronchodilator826

calcium metabolism20893

cardiotonic133235

chelator44

contraception981

cystic fibrosis413

diuretic642

erythropoiesis55

gastroprokinetic4121

hematopoiesis77

hemophilia1919

hemostatic44

hormone221210

hormone replacement therapy88

hyperphosphatemia55

hypnotic1212

hypocholesterolemic1341215

hypolipidemic817

immunomodulator4211

immunostimulant126321

immunosuppressant14653

irritable bowel syndrome5113

macular degeneration6411

male sexual dysfunction55

multiple sclerosis1042211

muscle relaxant104213

neuroleptic9162

al.,106that kinase modulation occurs in a large number of other diseases,and not just in cancer.

Thus,PTK inhibitors have a wide range of possible targets and, in the cases of some speci?c approved antitumor-directed kinase inhibitors,have a very large number of“targets”in the human kinome.Thus,sunitinib(5)a?ects a very considerable number of di?erent kinase“families”,whereas lapatinib(6)is restricted to one class,and the as yet unapproved PTKi selumetinib (AZD6244;7)appears to be quite speci?c.These e?ects can be seen in the?gures in the2015paper by Fabbro et al.106and are further elaborated on by Tilgada et al.,109demonstrating that the targets of PTKi’s are not just in cancer and related diseases.As previously,we have continued to extend the“/SM”category to cover other direct inhibitors/antagonists of the natural substrate/receptor interaction whether obtained by direct experiment or by in silico studies followed by direct assay in the relevant system.

Similarly,a number of new peptidic drug entities,although formally synthetic in nature,are simply produced by chemical synthetic methods rather than by the use of fermentation or extraction.In some cases,an end group might have been changed for ease of recovery.However,a number of compounds produced totally by synthesis are in fact isosteres of the peptidic substrate and are thus“natural product mimics”in the truest sense of the term.We gave some examples of this type of interplay in our2012review,in which we mentioned the path to the“sartans”.4

Derivation of Oral Renin Inhibitors.Expanding upon this aspect of chemistry and pharmacology,we now will show how the?rst orally active renin inhibitor was derived starting from pepstatin.In Scheme1we show an idealized representation of the angiotensin system pathway,showing the physiological route from renin(an aspartic proteinase)through to the angiotensin-converting enzyme(ACE),to yield the hexapeptide angiotensin II.It was knowledge that this enzyme is a zinc-containing carboxy-peptidase that enabled the Squibb group back in the 1970s to synthesize the pseudodipeptide captopril(8)as the?rst ACE inhibitor to be approved by the FDA.

However,the“prime target”in the system is inhibition of renin since that is the enzyme that starts the cascade,and,unlike ACE, it does not hydrolyze the“kinin”peptides(bradykinin,etc.). Renin was known to be an aspartic proteinase,and it could be inhibited by the bacterial peptide pepstatin(9).This compound contains the unusual amino acid statine,which contains as a dipeptide mimic a hydroxyethylene isostere,and it was the basis of a long-term project at Merck to synthesize renin inhibitors, and later HIV-protease inhibitors,based on this substituent mimicking the transition state of the aspartic proteinase/ substrate pair.110,111Although none of their peptide structures provided a renin inhibitor that was approved as a drug,their work demonstrated the potential for such substitutions to be e?ective drug leads,albeit from Ciba-Geigy(now Novartis),en route to an orally active renin inhibitor.The?rst of what were known as type-I inhibitors112contained the dipeptide isostere(2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid at the P1?P1′position and also mimicked angiotensinogen from residue P3to P1′using the nomenclature from Schetchter and Berger.113

The story of the search for orally active renin inhibitors, although formally nonpeptidic but still containing the hydroxy-ethylene transition state dipeptide isostere,was given in detail by Novartis scientists in two papers,demonstrating that the search

Table2.continued

indication total B N NB ND S S/NM S*S*/NM V nootropic835

osteoporosis6321

platelet aggregation inhibitor431

respiratory distress syndrome74111

urinary incontinence6231

vasodilation532

vulnerary8521

grand total13281895442683591495515694

a Diseases where≤3drugs approved1981?2014:234drugs fall into this category and are subdivided as follows:B,81;N,15;ND,46;S,47,S/NM. 15;S*,4;S*/NM,18.The diseases covered the following;5α-reductase inhibitor,ADHD,CAPS,CHF,CNS stimulant,Castleman’s disease, Crohn’s disease,Cushing’s syndrome,Fabry’s disease,Hunter syndrome,inborn errors of bile synthesis,in?ammatory bowel disease,Japanese encephalitis,Lambert-Eaton myasthenic syndrome,Lyme disease,acute MI,MMRC,Morquio A syndrome,PAH,PCP/toxoplasmosis,PNH, Pompe’s disease,Turner syndrome,abortifacient,acromelagy,alcohol deterrent,allergic rhinitis,anabolic metabolism,analeptic,anemia,antisickle cell anemia,antismoking,antiacne,antiathersclerotic,anticonvulsant,antidiarrheal,antidote,antiemphysemic,antihyperuricemia,antihypotensive, antinarcolepsy,antinarcotic,antinauseant,antiperistaltic,antiprogestogenic,antirheumatic,antisecretory,antisepsis,antiseptic,antispasmodic, antispastic,antitussive,antityrosinaemia,antixerostomia,atrial?brillation,benzodiazepine antagonist,β-lactamase inhibitor,blepharospasm,bone disorders,bone morphogenesis,bowel evacuant,cancer adjuvant,cardioprotective,cardiovascular disease,cartilage disorders,cervical dystonia, choleretic,chronic idiopathic constipation,cognition enhancer,congestive heart failure,constipation,coronary artery disease,cystinosis, cytoprotective,diabetic foot ulcers,diabetic neuropathies,digoxin toxicity,dispareunia,dry eye syndrome,dyslipidemia,dysuria,endometriosis, enzyme,expectorant,eye disorders,fertility inducer,free-running circadian disorder,gastroprotectant,genital warts,hematological,hemorrhage, hepatoprotectant,hereditary angioedema,homocystinuria,hyperammonemia,hypercholesterolemia(and familial),hyperparathyroidism, hyperphenylalaninemia,hypertriglyceridemia,hyperuricemia,hypoammonuric,hypocalciuric,hypogonadism,hyponatremia,idiopathic pulmonary ?brosis,idiopathic thrombocytopenia,immediate allergy,infertility(female),in?ammatory bowel disease,insecticide,insomnia,joint lubricant, lipodystrophy(and in HIV),lipoprotein disorders,lipoprotein lipase de?ciency,lupus erythematosus,mucolytic,mucopolysaccharidosis,mucositis, myleodysplasia,narcolepsy,nasal decongestant,neuropathic pain,neuroprotective,neutropenia,ocular in?ammation,opiate detoxi?cation,opiod-induced constipation,osteoarthritis,overactive bladder,ovulation,pancreatic disorders,pancreatitis,pertussis,photosensitizer,phytotoxicity in adults,pituitary disorders,porphyria,premature birth,premature ejaculation,progestogen,psychostimulant,pulmonary arterial hypertension, purpura fulminans,rattlesnake antivenom,reproduction,restenosis,schizophrenia,sclerosant,secondary hyperthryoidism,sedative,short bowel syndrome,skin photodamage,smoking cessation,strabismus,subarachnoid hemorrhage,thrombocytopenia,treatment of GH de?ciency,ulcerative colitis,urea cycle disorders,uremic pruritis,urolithiasis,vaccinia complications,varicella(chicken pox),vasoprotective,venous thromboembolism.

Table3.Antibacterial Drugs from1/1/1981to12/31/2014Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source raxibacumab ABthrax2012I336061B carumonam Amasulin1988ARMC24298N daptomycin Cubicin2003ARMC39347N fidaxomicin Dificid2011DT48(1)40N fosfomycin trometamol Monuril1988I112334N isepamicin Isepacin1988ARMC24305N micronomicin sulfate Sagamicin1982P091082N miokamycin Miocamycin1985ARMC21329N mupirocin Bactroban1985ARMC21330N netilimicin sulfate Netromicine1981I070366N RV-11Zalig1989ARMC25318N teicoplanin Targocid1988ARMC24311N apalcillin sodium Lumota1982I091130ND arbekacin Habekacin1990ARMC26298ND aspoxicillin Doyle1987ARMC23328ND astromycin sulfate Fortimicin1985ARMC21324ND azithromycin Sunamed1988ARMC24298ND aztreonam Azactam1984ARMC20315ND biapenem Omegacin2002ARMC38351ND cefbuperazone sodium Tomiporan1985ARMC21325ND cefcapene pivoxil Flomox1997ARMC33330ND cefdinir Cefzon1991ARMC27323ND cefditoren pivoxil Meiact1994ARMC30297ND cefepime Maxipime1993ARMC29334ND cefetamet pivoxil HCl Globocef1992ARMC28327ND cefixime Cefspan1987ARMC23329ND cefmenoxime HCl Tacef1983ARMC19316ND cefminox sodium Meicelin1987ARMC23330ND cefodizime sodium Neucef1990ARMC26300ND cefonicid sodium Monocid1984ARMC20316ND cefoperazone sodium Cefobis1981I127130ND ceforanide Precef1984ARMC20317ND cefoselis Wincef1998ARMC34319ND cefotetan disodium Yamatetan1984ARMC20317ND cefotiam HCl Pansporin1981I091106ND cefozopran HCl Firstcin1995ARMC31339ND cefpimizole Ajicef1987ARMC23330ND cefpiramide sodium Sepatren1985ARMC21325ND cefpirome sulfate Cefrom1992ARMC28328ND cefpodoxime proxetil Banan1989ARMC25310ND cefprozil Cefzil1992ARMC28328ND cefsoludin sodium Takesulin1981I091108ND ceftaroline fosamil acetate Teflaro2011DT48(1)40ND ceftazidime Fortam1983ARMC19316ND cefteram pivoxil Tomiron1987ARMC23330ND Ceftibuten Seftem1992ARMC28329ND ceftizoxime sodium Epocelin1982I070260ND ceftobiprole medocaril Zeftera2008ARMC44589ND ceftriaxone sodium Rocephin1982I091136ND cefuroxime axetil Zinnat1987ARMC23331ND cefuzonam sodium Cosmosin1987ARMC23331ND cetolozane/tazobactam Zerbaxa2014DT51(1)47ND clarithromycin Klaricid1990ARMC26302ND dalbavancin Dalavance2014DT51(!)47ND dalfopristin Synercid1999ARMC35338ND dirithromycin Nortron1993ARMC29336ND doripenem Finibax2005DNP1942ND ertapenem sodium Invanz2002ARMC38353ND erythromycin acistrate Erasis1988ARMC24301ND flomoxef sodium Flumarin1988ARMC24302ND flurithromycin ethylsuccinate Ritro1997ARMC33333ND

generic name trade name year introduced volume page source fropenam Farom1997ARMC33334ND imipenem/cilastatin Zienam1985ARMC21328ND lenampicillin HCI Varacillin1987ARMC23336ND loracarbef Lorabid1992ARMC28333ND meropenem Merrem1994ARMC30303ND moxalactam disodium Shiomarin1982I070301ND oritavancin Orbactiv2014DT51(1)47ND panipenem/betamipron Carbenin1994ARMC30305ND quinupristin Synercid1999ARMC35338ND retapamulin Altabax2007ARMC43486ND rifabutin Mycobutin1992ARMC28335ND rifamixin Normix1987ARMC23341ND rifapentine Rifampin1988ARMC24310ND rifaximin Rifacol1985ARMC21332ND rokitamycin Ricamycin1986ARMC22325ND roxithromycin Rulid1987ARMC23342ND sultamycillin tosylate Unasyn1987ARMC23343ND tazobactam sodium Tazocillin1992ARMC28336ND telavancin HCl Vibativ2009DNP2315ND telithromycin Ketek2001DNP1535ND temocillin disodium Temopen1984ARMC20323ND tigecycline Tygacil2005DNP1942ND balafloxacin Q-Roxin2002ARMC38351S bedaquiline Sirturo20121386239S besifloxacin Besivance2009DNP2320S ciprofloxacin Ciprobay1986ARMC22318S enoxacin Flumark1986ARMC22320S finafloxacin hydrochloride Xtoro2014DT51(1)48S fleroxacin Quinodis1992ARMC28331S garenoxacin Geninax2007ARMC43471S gatilfloxacin Tequin1999ARMC35340S gemifloxacin mesilate Factive2003ARMC40458S grepafloxacin Vaxor1997DNP1123S levofloxacin Floxacin1993ARMC29340S linezolid Zyvox2000DNP1421S lomefloxacin Uniquin1989ARMC25315S moxifloxacin HCl Avelox1999ARMC35343S nadifloxacin Acuatim1993ARMC29340S nemonoxacin Taigexyn2014DT51(1)48S norfloxacin Noroxin1983ARMC19322S ofloxacin Tarivid1985ARMC21331S pazufloxacin Pasil2002ARMC38364S pefloxacin mesylate Perflacine1985ARMC21331S prulifloxacin Sword2002ARMC38366S rufloxacin hydrochloride Qari1992ARMC28335S sitafloxacin hydrate Gracevit2008DNP2215S sparfloxacin Spara1993ARMC29345S taurolidine Taurolin1988I107771S tedizolid phosphate sodium Sivextro2014DT51(1)47S temafloxacin hydrochloride Temac1991ARMC27334S tosufloxacin Ozex1990ARMC26310S trovafloxacin mesylate Trovan1998ARMC34332S brodimoprin Hyprim1993ARMC29333S*/NM

Bexsero2013DT50(1)69V

Prevenar132009DNP2317V

Quattrovac2012I770186V

Synflorix2009DNP2317V

Typbar2013DT50(1)68V ACWY meningoccal PS vaccine Mencevax1981I420128V

BK-4SP Tetrabik2012I697562V botulism antitoxin Bat2013DT50(1)77V

involved signi?cant computerized structure?activity relation-ships using the crystal structure of human renin to optimize the chemistry,before?nally leading to the drug candidate,SPP-100, which became the drug aliskiren(10)and gained FDA approval in March2007and EMA approval in August2007.The?rst paper,in2000,114gave the chemical basis for the initial discoveries of pseudopeptidic agents and the use of structure-based drug design with modi?cations around the initial type-I inhibitor(CGP38′560;11).The second paper,published in 2003,115gave the next chapter in the story,the work leading up to aliskiren.Finally,a thorough analysis of the various molecules and routes leading to aliskiren was published by Novartis scientists in2010,and this should be consulted for the full story.116

Also of interest are some recent publications that under certain conditions could almost be considered as potential for “repurposing”of this drug and perhaps others with the same target.Following a study on the conformation of aliskiren in solution and when bound to its receptor,by Politi et al.,in 2011117the data were used to calculate binding of aliskiren to a model of the HIV protease(an aspartic proteinase).This study also demonstrated that the FDA-approved(2013)SGLT-2 inhibitor canagli?ozin(12)and the approved HIV protease inhibitor darunavir(13)may have cross-activities in renin inhibition as well as their regular approved pharmacological targets,thus potentially repurposing these compounds.118 Biologically Active Peptides.A review covering the preparation of biologically active peptides was published in 2014and makes interesting reading when the methodologies are compared with those covering the synthesis of pseudopeptides that inhibit aspartic proteinases.119

Modi?cations of Natural Products by Combinatorial Methods.These techniques often produce entirely di?erent compounds that may bear little if any resemblance to the original lead,but are legitimately assignable to the“/NM”category.In addition to the citations given in our previous reviews covering these methodologies,there have been some recent publications that can be consulted in order to demonstrate how“privileged structures from Nature”are demonstrated sources of molecular skeletons around which one may build libraries.120?123

Overview of Results.The data that have been analyzed in a variety of ways are presented as a series of bar graphs and pie charts and two major tables in order to establish the overall picture and then are further subdivided into some major therapeutic areas using a tabular format.The time frame covered is the34years from January1,1981,to December31,2014.?New Approved Drugs:From all source categories;pie

chart(Figure1)

?New Approved Drugs:By source/year;bar graph(Figure

?Sources of All NCEs:Where four or more drugs were

approved per medical indication,their sources are shown,

and listings of diseases with≤3approved drugs(Table2)?Sources of Small-Molecule NCEs:All subdivisions;pie

chart(Figure3)

?Sources of Small-Molecule NCEs:By source/year;bar

graph(Figure4)

?Total Small Molecules:By year;point chart(Figure5)?N/NB/ND and S*Categories:By year;bar graph(Figure

?Percentage of N*Sources:By year;bar graph(Figure7)?Antibacterial Drugs:Generic and trade names,year,

reference,and source(Table3)

?Antifungal Drugs:Generic and trade names,year,

reference,and source(Table4)

?Antiviral Drugs:Generic and trade names,year,reference,

and source(Table5)

?Antiparasitic Drugs:Generic and trade names,year,

reference,and source(Table6)

?Anti-infective Drugs:All molecules,source,and numbers

(Table7)

?Anti-infective Drugs:Small molecules,source,and

numbers(Table8)

?Anticancer Drugs:Generic and trade names,year,

reference by source(Table9;Figure8all drugs pie

chart;Figure9,small molecules pie chart)

?All Anticancer Drugs(very late1930s?12/2014):Generic

and trade names,year,and reference by source(Table10;

Figure10pie chart;Figure11,bar graph)

generic name trade name year introduced volume page source DTPw-HepB-Hib Quinvaxem2006DNP2026V DTP vaccines Daptacel2002I319668V H.influenzae b vaccine Hibtitek1989DNP0324V H.influenzae b vaccine Prohibit1989DNP0324V hexavalent vaccine Hexavac2000DNP1422V hexavalent vaccine Infantrix HeXa2000DNP1422V

Hib-MenCY-TT Menhibrix2012I421742V MCV-4Menactra2005DNP1943V MenACWY-CRM Menveo2010I341212V MenACWY-TT Nimenrix2012I421745V meningitis b vaccine MeNZB2004DNP1829V meningococcal vaccine Menigetec1999DNP1422V meningococcal vaccine NeisVac-C2000DNP1422V meningococcal vaccine Menjugate2000DNP1422V MnB rLP2086Trumenba2014DT51(1)51V oral cholera vaccine Orochol1994DNP0830V pneumococcal vaccine Prevnar2000DNP1422V PsA-TT MenAfriVac2010I437718V

Vi polysaccharide typhoid vaccine Typherix1998DNP1235V

?Antidiabetic Drugs:Generic and trade names,year, reference,and source(Table11)

The extensive data sets shown in the?gures and tables referred to above continue to highlight the continuing role that natural products and structures derived from or related to natural products from all sources have played,and continue to play,in the development of the current therapeutic armamentarium of the physician.Inspection of the data shows the continued important role for natural products in spite of the greatly reduced level of natural-products-based drug discovery programs in major pharmaceutical houses.

Inspection of the rate of NCE approvals as shown in Figures2 and4?7demonstrate that even in2014the natural products?eld is still producing,or is involved in,～40%of all small molecules in the years2000?2008,with a drop to～20%in2009,followed by a rebound to45%in2010,and then?uctuation between a low of ～13%in2013to between25%and30%in the other years of the second decade of the21st century.The mean and standard deviation for these15years are34±9%,without including any of the natural-product-inspired classi?cations(“S*”,“S*/NM”,and “S/NM”).

As was shown in the2012review,a signi?cant number of all NCEs still fall into the categories of biological(“B”)or vaccines (“V”),with351of1562,or23%(di?ers slightly from Figure1 due to rounding),over the full34-year period,and it is admitted that not all of the vaccines approved in these34years have been identi?ed.We hope that in the last14or15years a majority have been captured,although some of the more obscure anti-in?uenza variants may not have been.Thus,the proportion of approved vaccines may well be higher over the longer time frame. Inspection of Figure2shows the signi?cant proportion that these two categories hold in the number of approved drugs from2000, where,in some years,these categories accounted for ca.50%of all approvals.If the three“N”categories are included,then the proportions of formally nonsynthetics are even higher for these years,although this?gure would increase if the“S*”variants are included.

De Novo Combinatorial Drugs.As mentioned earlier,in spite of many years of work by the pharmaceutical industry devoted to high-throughput screening of very signi?cant numbers of combinatorial chemistry products(cf.Macar-ron’s20,24,25and Wassermann’s26papers on the industrial perspectives),during this time period,only two approved drugs could be found that fall under the de novo combinatorial category,sorafenib(1)and ataluren(2),with vemurafenib(3) potentially falling into this category due to the use of fragment-based methods.

Natural Product Mimics.Overall,of the1562NCEs covering all diseases/countries/sources in the years01/1981?12/2014,and using the“NM”classi?cations introduced in our 2003review,2the334compounds falling into these categories accounted for21%,or if using just the small molecules where the divisor drops to1211,the?gure becomes28%.This demonstrates the in?uence of“other than formal synthetics”on drug discovery and approval(Figures1and3).In the2012 review,the corresponding?gures were～20%for all drugs and 25%for small molecules.4

Disease Area Breakdowns.It should be noted before proceeding with this and subsequent sections that we altered some of the“disease nomenclature terminology”,for example, rolling in all antidiabetic treatments under one category rather than subdividing into types1and2.Thus,a direct comparison of Table2in this review with its predecessor tables needs to take such modi?cations into account.Inspection of Table2 demonstrates that,overall,the major disease areas that have been investigated(in terms of numbers of drugs approved)in the pharmaceutical industry continue to be infectious diseases (microbial,parasitic,and viral),cancer,hypertension,anti-diabetic,and in?ammation,all with over50approved drug

Table4.Antifungal Drugs from1/1/1981to12/31/2010 Organized Alphabetically by Generic Name within Source

generic name trade name

year

introduced volume page source

interferon

gamma-n1

OGamma1001996DNP1013B anidulafungin Eraxis2006DNP2024ND caspofungin

acetate

Cancidas2001DNP1536ND

micafungin sodium Fungard2002ARMC

360ND

amorol?ne hydrochloride Loceryl1991ARMC

322S

butoconazole Femstat1986ARMC

318S

ciclopirox

olamine

Loprox1982I070449S

cloconazole HCI Pilzcin1986ARMC

318S eberconazole Ebernet2005DNP1942S e?naconazole Jublia2013DT

50(1)

66S

fenticonazole nitrate Lomexin1987ARMC

334S

?uconazole Di?ucan1988ARMC

303S

?utrimazole Micetal1995ARMC

343S fos?uconazole Prodif2003DNP1749S itraconazole Sporanox1988ARMC

305S ketoconazole Nizoral1981I116505S lanoconazole Astat1994ARMC

302S luliconazole Lulicon2005DNP1942S nafti?ne HCI Exoderil1984ARMC

321S

neticonazole HCI Atolant1993ARMC

341S

oxiconazole nitrate Oceral1983ARMC

322S

posaconazole Noxa?l2005DNP1942S

sertaconazole nitrate Dermo?x1992ARMC

336S

sita?oxacin

hydrate

Gracevit2008DNP2215S

sulconazole nitrate Exelderm1985ARMC

332S

tavaborole Kerydin2014DT

51(1)

51S

terconazole GynoTerazol1983ARMC

324S

tioconazole Trosyl1983ARMC

324S

voriconazole Vfend2002ARMC

370S

butena?ne hydrochloride Mentax1992ARMC

327S/

liranaftate Zefnart2000DNP1421S/

terbina?ne hydrochloride Lamisil1991ARMC

334S/

Table5.Antiviral Drugs from1/1/1981to12/31/2014Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source

Oralgen2007I415378B IGIV-HB Niuliva2009DNP2316B immunoglobulin intravenous Gammagard Liquid2005I231564B interferon alfa Alfaferone1987I215443B interferon alfa-2b Viraferon1985I165805B interferon alfacon-1Infergen1997ARMC33336B interferon alfa-n1Wellferon1986I125561B interferon alfa-n3Alferon N1990DNP04104B interferon beta Frone1985I115091B palivizumab Synagis1998DNP1233B peginterferon alfa-2a Pegasys2001DNP1534B peginterferon alfa-2b Pegintron2000DNP1418B resp syncytial virus IG RespiGam1996DNP1011B thymalfasin Zadaxin1996DNP1011B enfuvirtide Fuzeon2003ARMC39350ND laninamivir octanoate Inavir2010I340894ND oseltamivir Tamiflu1999ARMC35346ND zanamivir Relenza1999ARMC35352ND daclatasvir dihydrochloride Daklinza2014DT51(1)48S dasabuvir Exviera2014DT51(1)50S delavirdine mesylate Rescriptor1997ARMC33331S dolutegravir Tivicay2013DT50(1)63S efavirenz Sustiva1998ARMC34321S elvitegravir Viteka2013DT50(1)63S foscarnet sodium Foscavir1989ARMC25313S imiquimod Aldara1997ARMC33335S maraviroc Celsentri2007ARMC43478S nevirapine Viramune1996ARMC32313S propagermanium Serosion1994ARMC30308S raltegravir potassium Isentress2007ARMC43484S rilpivirine hydrochloride Edurant2011DT48(1)41S rimantadine HCI Roflual1987ARMC23342S asunaprevir Sunvepra2014DT51(1)48S/NM cobicistat Tybost2013DT50(1)63S/NM darunavir Prezista2006DNP2025S/NM ledipasvir Harvoni2014DT51(1)48S/NM peramivir PeramiFlu2010I273549S/NM abacavir sulfate Ziagen1999ARMC35333S* acyclovir Zovirax1981I091119S* adefovir dipivoxil Hepsera2002ARMC38348S* cidofovir Vistide1996ARMC32306S* clevudine Levovir2007ARMC43466S* didanosine Videx1991ARMC27326S* emtricitabine Emtriva2003ARMC39350S* entecavir Baraclude2005DNP1939S* epervudine Hevizos1988I157373S* etravirine Intelence2008DNP2215S* famciclovir Famvir1994ARMC30300S* ganciclovir Cymevene1988ARMC24303S* inosine pranobex Imunovir1981I277341S* lamivudine Epivir1995ARMC31345S* penciclovir Vectavir1996ARMC32314S* sofosbuvir Solvadi2013DT50(1)64S* sorivudine Usevir1993ARMC29345S* stavudine Zerit1994ARMC30311S* telbividine Sebivo2006DNP2022S* tenofovir disoproxil fumarate Viread2001DNP1537S* valaciclovir HCl Valtrex1995ARMC31352S* valganciclovir Valcyte2001DNP1536S* zalcitabine Hivid1992ARMC28338S* zidovudine Retrovir1987ARMC23345S*

generic name trade name year introduced volume page source amprenavir Agenerase1999ARMC35334S*/NM atazanavir Reyataz2003ARMC39342S*/NM boceprevir Victrelis2011DT48(1)41S*/NM favipiravir Avigan2014DT51(1)50S*/NM fomivirsen sodium Vitravene1998ARMC34323S*/NM fosamprenevir Lexiva2003ARMC39353S*/NM indinavir sulfate Crixivan1996ARMC32310S*/NM lopinavir Kaletra2000ARMC36310S*/NM neflinavir mesylate Viracept1997ARMC33340S*/NM ombitasvir Viekira Pak2014DT51(1)50S*/NM paritaprevir Viekira Pak2014DT51(1)50S*/NM ritonavir Norvir1996ARMC32317S*/NM saquinavir mesylate Invirase1995ARMC31349S*/NM simeprevir Sovirad2013DT50(1)63S*/NM telaprevir Incivek2011DT48(1)41S*/NM tipranavir Aptivus2005DNP1942S*/NM vaniprevir Vanihep2014DT51(1)49S*/NM

ACAM-20002007I328985V

Bilive2005DNP1943V

Celtura2009DNP2317V

Celvapan2009DNP2317V

Daronix2007I427024V

Fluval P2009DNP2317V

Fluzone Quadrivalent2013DT50(1)68V

Focetria2009DNP2317V

Grippol Neo2009DNP2316V

Hexyon2013DT50(1)69V

Imvanex2013DT50(1)69V

Optaflu2007I410266V

Pandremix2009DNP2317V

Panenza2009DNP2317V

Panflu2008DNP2216V

Vaxiflu-S2010I698015V

VariZIG2005I230590V

Vepacel2012I768351V

9vHPV Gardasil92014DT51(1)52V HPV vaccine Gardasil2006DNP2026V

anti-Hep B immunoglobulin HepaGam B2006DNP2027V antirabies vaccine Rabirix2006DNP2027V attenuated chicken pox vaccine Merieux Varicella1993DNP0731V BBIL/JEV Jenvac2013DT50(1)68V chimerivax-JE Imojev2012I292954V CSL-401Panvax2008DNP2216V FLU-Q-QIV Fluarix Quadrivalent2012DT50(1)68V GSK-1562902A Prepandrix2008DNP2216V GSK-2282512A Fluarix Quadrivalent2012I709665V

H5N1avian flu vaccine2007I440743V hepatitis a vaccine Aimmugen1995DNP0923V hepatitis a vaccine Havrix1992DNP0699V hepatitis a vaccine Vaqta1996DNP1011V hepatitis b vaccine Biken-HB1993DNP0731V hepatitis b vaccine Bio-Hep B2000DNP1422V hepatitis b vaccine Engerix B1987I137797V hepatitis b vaccine Fendrix2005DNP1943V hepatitis b vaccine Hepacure2000DNP1422V hepatitis b vaccine Meinyu1997DNP1124V hepatitis a and b vaccine Ambirix2003I334416V

HN-VAC HNVAC2010I684608V inact hepatitis a vaccine Avaxim1996DNP1012V influ A(H1N1)monovalent2010I678265V influenza vaccine Invivac2004I391186V

therapies.It should be noted,however,that the numbers of approved drugs/disease do not correlate with the “value ”as measured by sales.For example,the best-selling drug of all at the moment is atorvastatin (Lipitor),a hypocholesterolemic descended directly from a microbial natural product,which sold over (U.S.)$11billion in 2004,and,if one includes sales by P ?zer and Astellas Pharma over the 2004to 2014time frames,

sales have hovered in the range (U.S.)$12?14billion depending upon the year.However,this ?gure is almost sure to be eclipsed in short order by the new drugs approved for hepatitis C treatments such as sofosbuvir (14),which is a masked nucleotide,but is currently classi ?ed by us as an “S *”,although it is obviously based upon an NP sca ?old.

Anti-infectives in General.This is the major category by far including antiviral vaccines,with 326(25%)of the total drug entities (1328for indications ≥4;Table 2)falling into this one major human disease area.On further analysis (Tables 7and 8),the in ?uence of biologicals and vaccines in this disease complex is such that only 22%are synthetic in origin (Table 7).If one considers only small molecules (reducing the total by 105to 221;Table 8),then the synthetic ?gure goes up to 33%,marginally greater than in our 2012report.4As reported previously,1?4these synthetic drugs tend to be of two basic chemotypes,the azole-based antifungals and the quinolone-based antibacterials.

Anitbacterial Agents.Nine small-molecule drugs were approved in the antibacterial area from January 2011to December 2014.One,?daxomycin (15),was classi ?ed as an “N ”;four were classi ?ed as “ND ”,with the ?rst,ceftaroline (16),being a semisynthetic cephalosporin,the second being another cephalosporin derivative,cetolozane (17a )in combination with

generic name

trade name year introduced

volume page source influenza vaccine Optaflu 2008DNP 2216V influenza virus (live)FluMist 2003ARMC 39353V influenza virus vaccine Afluria

2007I 449226V KD-295

2014DT 51(1)52V measles/rubella vaccine 2011DT 48(1)44V Medi-3250FluMist Quadrivalent 2012I 669909V MR vaccine

Mearubik 2005DNP 1944V rec hepatitis B vaccine Supervax 2006DNP 2027V rotavirus vaccine Rotarix 2005DNP 1829V rotavirus vaccine Rota-Shield 1998DNP 1235V rotavirus vaccine Rotateq 2006DNP 2026V rubella vaccine

Ervevax 1985I 115078V varicella virus vaccine Varivax 1995DNP 0925V VCIV

PreFluCel 2010I 444826V zoster vaccine live

Zostavax

2006

DNP 20

Table 6.Antiparasitic Drugs from 1/1/1981to 12/31/2014Organized Alphabetically by Generic Name within Source

generic name trade name year introduced volume page source artemisinin Artemisin 1987ARMC 23327N ivermectin Mectizan 1987ARMC 23336N arteether Artemotil 2000DNP 1422

ND artemether Artemetheri 1987I 90712ND artesunate

Arinate 1987I 91299ND e ?ornithine HCl Ornidyl 1990DNP 04104ND me ?oquine HCI Fansimef 1985ARMC 21329

ND albendazole Eskazole 1982I 129625S delamanid Deltyba 2014DF 51(1)48S halofantrine Halfan 1988ARMC 24304

S lumefantrine ?

1987I 269095S quinfamide Amenox 1984ARMC 20322S atovaquone Mepron 1992ARMC 28326S *bulaquine/chloroquine Aablaquin 2000DNP 1422

S *trichomonas vaccine

Gynatren

1986

I 125543

Table 7.All Anti-infective (Antibacterial,Fungal,Parasitic,and Viral)Drugs (n =326)

indication total B N ND S S/NM S *S */NM V antibacterial 14111171291

28antifungal 3213253antiparasitic 1525521antiviral 138144145241760total

326161383738261889percentage

100

4.9

4.0

25.5

22.4

2.4

8.0

5.5

27.3

Table 8.Small-Molecule Anti-infective (Antibacterial,Fungal,Parasitic,and Viral)Drugs (n =221)

indication total N ND S S/NM S *

S */NM antibacterial 1121171291

antifungal 313253antiparasitic 142552antiviral 6441452417total

22113837382618percentage

100

5.9

37.6

33.0

3.6

11.8

8.1

Table9.Anticancer Drugs from1/1/1981to12/31/2014Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source

Rexin-G2007I346431B 131I-chTNT2007I393351B alemtuzumab Campath2001DNP1538B bevacizumab Avastin2004ARMC40450B blinatumomab Blincyto2014DT51(1)55B catumaxomab Removab2009DNP2318B celmoleukin Celeuk1992DNP06102B cetuximab Erbitux2003ARMC39346B denileukin diftitox Ontak1999ARMC35338B H-1012005DNP1946B ibritumomab Zevalin2002ARMC38359B interferon alfa2a Roferon-A1986I204503B interferon,gamma-1a Biogamma1992ARMC28332B interleukin-2Proleukin1989ARMC25314B ipilimumab Yervoy2011DT48(1)45B mobenakin Octin1999ARMC35345B mogamulizumab Poteligeo2012I433141B nimotuzumab BIOMAb EFGR2006DNP2029B nivolumab Optivo2014DT51(1)56B obinutuzumab Gazyva2013DT50(1)70B ofatumumab Arzerra2009DNP2318B panitumumab Vectibix2006DNP2028B pegaspargase Oncaspar1994ARMC30306B pembrolizumab Keytruda2014DT51(1)56B pertuzumab Omnitarg2012I300439B racotumomab Vaxira2013DT50(1)72B ramucirumab Cyramza2014DT51(1)55B rituximab Rituxan1997DNP1125B sipuleucel-T Provenge2010I259673B tasonermin Beromun1999ARMC35349B teceleukin Imumace1992DNP06102B tositumomab Bexxar2003ARMC39364B trastuzumab Herceptin1998DNP1235B aclarubicin Aclacin1981P090013N aminolevulinic acid HCl Levulan2000DNP1420N angiotensin II Delivert1994ARMC30296N arglabin?1999ARMC35335N homoharringtonine Ceflatonin2012I090682N ingenol mebutate Picato2012I328987N masoprocol Actinex1992ARMC28333N paclitaxel Taxol1993ARMC29342N paclitaxel nanoparticles Abraxane2005DNP1945N paclitaxel nanoparticles Nanoxel2007I422122N paclitaxel nanoparticles Genexol-PM2007I811264N paclitaxel nanoparticles PICN2014DT51(1)58N pentostatin Nipent1992ARMC28334N peplomycin Pepleo1981I090889N romidepsin Istodax2010DNP2318N trabectedin Yondelis2007ARMC43492N solamargines Curaderm1989DNP0325NB abiratenone acetate Zytiga2011DT48(1)44ND alitretinoin Panretin1999ARMC35333ND aminolevulinic-CO2CH3Metvix2001DNP1534ND amrubicin HCl Calsed2002ARMC38349ND belotecan hydrochloride Camtobell2004ARMC40449ND bf-200ala Ameluz2012I431098ND brentuximab vedotin Adcetris2011DT48(1)45ND cabazitaxel Jevtana2010I287186ND carfilzomib Kyprolis2012I413092ND cladribine Leustatin1993ARMC29335ND cytarabine ocfosfate Starsaid1993ARMC29335ND

generic name trade name year introduced volume page source docetaxel Taxotere1995ARMC31341ND elliptinium acetate Celiptium1983I091123ND epirubicin HCI Farmorubicin1984ARMC20318ND eribulin Halaven2010I287199ND etoposide phosphate Etopophos1996DNP1013ND exemestane Aromasin1999DNP1346ND formestane Lentaron1993ARMC29337ND fulvestrant Faslodex2002ARMC38357ND gemtuzumab ozogamicin Mylotarg2000DNP1423ND hexyl aminolevulinate Hexvix2004I300211ND idarubicin hydrochloride Zavedos1990ARMC26303ND irinotecan hydrochloride Campto1994ARMC30301ND ixabepilone Ixempra2007ARMC43473ND mifamurtide Junovan2010DNP2318ND miltefosine Miltex1993ARMC29340ND pirarubicin Pinorubicin1988ARMC24309ND pralatrexate Folotyn2009DNP2318ND talaporfin sodium Laserphyrin2004ARMC40469ND temsirolimus Toricel2007ARMC43490ND topotecan HCl Hycamptin1996ARMC32320ND trastuzumab emtansine Kadcyla2013DT50(1)69ND triptorelin Decapeptyl1986I090485ND valrubicin Valstar1999ARMC35350ND vapreotide acetate Docrised2004I135014ND vinflunine Javlor2010I219585ND vinorelbine Navelbine1989ARMC25320ND zinostatin stimalamer Smancs1994ARMC30313ND aminoglutethimide Cytadren1981I070408S amsacrine Amsakrin1987ARMC23327S arsenic trioxide Trisenox2000DNP1423S bisantrene hydrochloride Zantrene1990ARMC26300S carboplatin Paraplatin1986ARMC22318S flutamide Drogenil1983ARMC19318S fotemustine Muphoran1989ARMC25313S heptaplatin/SK-2053R Sunpla1999ARMC35348S lobaplatin Lobaplatin1998DNP1235S lonidamine Doridamina1987ARMC23337S miriplatin hydrate Miripla2010DNP2317S nedaplatin Aqupla1995ARMC31347S nilutamide Anadron1987ARMC23338S olaparib Lynparza2014DT51(1)56S oxaliplatin Eloxatin1996ARMC32313S plerixafor hydrochloride Mozobil2009DNP2217S pomalidomide Pomalyst2013DT50(1)70S porfimer sodium Photofrin1993ARMC29343S ranimustine Cymerine1987ARMC23341S sobuzoxane Parazolin1994ARMC30310S sorafenib Nexavar2005DNP1945S vismodegib Erivedge2012I473491S zoledronic acid Zometa2000DNP1424S alectinib hydrochloride Alecensa2014DT51(1)56S/NM anastrozole Arimidex1995ARMC31338S/NM apatinib mesylate Aitan2014DT51(1)56S/NM bicalutamide Casodex1995ARMC31338S/NM bortezomib Velcade2003ARMC39345S/NM camostat mesylate Foipan1985ARMC21325S/NM ceritinib Zykadia2014DT51(1)55S/NM dasatinib Sprycel2006DNP2027S/NM enzalutamide Xtandi2012I438422S/NM erlotinib hydrochloride Tarceva2004ARMC40454S/NM fadrozole HCl Afema1995ARMC31342S/NM

the well-knownβ-lactamase inhibitor tazobactam(17b);the third was the modi?ed glycopeptide dalvabancin(18);and the fourth was another of this class,oritavancin(19).The two synthetic molecules included the?rst novel anti-TB sca?old for many years,bedaquiline(20),and another“?oxacin”,?na?ox-acin(21).Overall,in the antibacterial area,as shown in Table7, small molecules account for112agents,with“N”and“ND”compounds accounting for just over73%of the approved agents.

What should make biomedical scientists and physicians involved in antibacterial research in academia or industry very nervous is the recent report from Liu et al.,124in the journal Lancet Infectious Disease in the middle of November2015,where they reported that the class of compounds used e?ectively as the last resort(the peptidic colistins)now have a resistance determinant known as mcr-1appearing in microbes in treated patients and animals.

generic name trade name year introduced volume page source gefitinib Iressa2002ARMC38358S/NM imatinib mesilate Gleevec2001DNP1538S/NM lapatinib ditosylate Tykerb2007ARMC43475S/NM letrazole Femara1996ARMC32311S/NM nilotinib hydrochloride Tasigna2007ARMC43480S/NM pazopanib Votrient2009DNP2318S/NM sunitinib malate Sutent2006DNP2027S/NM temoporfin Foscan2002I158118S/NM toremifene Fareston1989ARMC25319S/NM azacytidine Vidaza2004ARMC40447S* capecitabine Xeloda1998ARMC34319S* carmofur Mifurol1981I091100S* clofarabine Clolar2005DNP1944S* decitabine Dacogen2006DNP2027S* doxifluridine Furtulon1987ARMC23332S* enocitabine Sunrabin1983ARMC19318S* fludarabine phosphate Fludara1991ARMC27327S* gemcitabine HCl Gemzar1995ARMC31344S* mitoxantrone HCI Novantrone1984ARMC20321S* nelarabine Arranon2006ARMC42528S* pixantrone dimaleate Pixuri2012I197776S* tipiracil hydrochloride Lonsurf2014DT51(1)58S* abarelix Plenaxis2004ARMC40446S*/NM afatinib Gilotrif2013DT50(1)69S*/NM axitinib Inlyta2012I38296S*/NM belinostat Beleodaq2014DT51(1)56S*/NM bexarotene Targretine2000DNP1423S*/NM bosutinib Bosulif2012I301996S*/NM cabozantinib S-malate Cometriq2012I379934S*/NM crizotinib Xalkori2011DT48(1)45S*/NM dabrafenib mesilate Tafinlar2013DT50(1)69S*/NM degarelix Firmagon2009DNP2216S*/NM ibrutinib Imbruvica2013DT50(1)71S*/NM idelalisib Zydelig2014DT51(1)54S*/NM pemetrexed disodium Alimta2004ARMC40463S*/NM ponatinib Iclusig2013DT50(1)70S*/NM radotinib Supect2012I395674S*/NM raltiterxed Tomudex1996ARMC32315S*/NM regorafenib Stivarga2012I395674S*/NM ruxolitinib phosphate Jakafi2011DT48(1)47S*/NM tamibarotene Amnoid2005DNP1945S*/NM temozolomide Temodal1999ARMC35350S*/NM trametinib DMSO Mekinist2013DT50(1)69S*/NM vandetanib Caprelsa2011DT48(1)45S*/NM vemurafenib Zeboraf2011DT48(1)45S*/NM vorinostat Zolinza2006DNP2027S*/NM

Cervarix2007I309201V autologous tumor cell-BCG OncoVAX2008DNP2217V

bcg live TheraCys1990DNP04104V melanoma theraccine Melacine2001DNP1538V vitespen Oncophage2008DNP2217V

Table10.All Anticancer Drugs(Late1930s to12/31/2014)Organized Alphabetically by Generic Name within Source generic name year introduced reference page source 131I-chTNT2007I393351B alemtuzumab2001DNP1538B aldesleukin1992ARMC25314B bevacizumab2004ARMC40450B catumaxomab2009DNP2318B celmoleukin1992DNP06102B cetuximab2003ARMC39346B denileukin diftitox1999ARMC35338B H-1012005DNP1946B ibritumomab2002ARMC38359B interferon alfa2a1986I204503B interferon,gamma-1a1992ARMC28332B interleukin-21989ARMC25314B ipilimumab2011DT48(1)45B mobenakin1999ARMC35345B mogamulizumab2012I433141B nimotuzumab2006DNP2029B nivolumab2014DT51(1)56B obinutuzumab2013DT50(1)70B ofatumumab2009DNP2318B panitumumab2006DNP2028B pegaspargase1994ARMC30306B pembrolizumab2014DT51(1)56B pertuzumab2012I300439B racotumomab2013DT50(1)72B ramucirumab2014DT51(1)55B Rexin-G(trade name)2007I346431B rituximab1997DNP1125B sipuleucel-T2010I259673B tasonermin1999ARMC35349B teceleukin1992DNP06102B tositumomab2003ARMC39364B trastuzumab1998DNP1235B PICN(Trade Name)2014DT51(1)58N aclarubicin1981I090013N actinomycin D1964FDA N angiotensin II1994ARMC30296N arglabin1999ARMC35335N asparaginase1969FDA N bleomycin1966FDA N carzinophilin1954Japan Antibiotics N chromomycin A31961Japan Antibiotics N daunomycin1967FDA N doxorubicin1966FDA N homoharringtonine2012I090682N ingenol mebutate2012I328987N leucovorin1950FDA N masoprocol1992ARMC28333N mithramycin1961FDA N mitomycin C1956FDA N neocarzinostatin1976Japan Antibiotics N paclitaxel1993ARMC29342N paclitaxel nanopart(Abraxane)2005DNP1945N paclitaxel nanopart(Nanoxel)2007I422122N paclitaxel nanopart(Genexol-PM)2007I811264N pentostatin1992ARMC28334N peplomycin1981I090889N romidepsin2010DNP2318N sarkomycin1954FDA N streptozocin pre-1977Carter N testosterone pre-1970Cole N

generic name year introduced reference page source trabectedin2007ARMC43492N vinblastine1965FDA N vincristine1963FDA N solamargines1989DNP0325NB abiratenone acetate2011DT48(1)44ND alitretinoin1999ARMC35333ND aminolevulinic-CO2CH32001DNP1534ND amrubicin HCl2002ARMC38349ND belotecan hydrochloride2004ARMC40449ND

bf-200ala2012I431098ND brentuximab vedotin2011DT48(1)45ND cabazitaxel2010I287186ND calusterone1973FDA ND carfilzomib2012I413092ND cladribine1993ARMC29335ND cytarabine ocfosfate1993ARMC29335ND dexamethasone1958FDA ND docetaxel1995ARMC31341ND dromostanolone1961FDA ND elliptinium acetate1983P091123ND epirubicin HCI1984ARMC20318ND eribulin2010I287199ND estramustine1980FDA ND ethinyl estradiol pre-1970Cole ND etoposide1980FDA ND etoposide phosphate1996DNP1013ND exemestane1999DNP1346ND fluoxymesterone pre-1970Cole ND formestane1993ARMC29337ND fosfestrol pre-1977Carter ND fulvestrant2002ARMC38357ND gemtuzumab ozogamicin2000DNP1423ND hexyl aminolevulinate2004I300211ND histrelin2004I109865ND hydroxyprogesterone pre-1970Cole ND idarubicin hydrochloride1990ARMC26303ND irinotecan hydrochloride1994ARMC30301ND ixabepilone2007ARMC43473ND medroxyprogesterone acetate1958FDA ND megesterol acetate1971FDA ND methylprednisolone1955FDA ND methyltestosterone1974FDA ND mifamurtide2010DNP2318ND miltefosine1993ARMC29340ND mitobronitol1979FDA ND nadrolone phenylpropionate1959FDA ND norethindrone acetate pre-1977Carter ND pirarubicin1988ARMC24309ND pralatrexate2009DNP2318ND prednisolone pre-1977Carter ND prednisone pre-1970Cole ND talaporfin sodium2004ARMC40469ND temsirolimus2007ARMC43490ND teniposide1967FDA ND testolactone1969FDA ND topotecan HCl1996ARMC32320ND trastuzumab emtansine2013DT50(1)69ND triamcinolone1958FDA ND triptorelin1986I090485ND valrubicin1999ARMC35350ND vapreotide acetate2004I135014ND

generic name year introduced reference page source vindesine1979FDA ND vinflunine2010I219585ND vinorelbine1989ARMC25320ND zinostatin stimalamer1994ARMC30313ND amsacrine1987ARMC23327S arsenic trioxide2000DNP1423S bisantrene hydrochloride1990ARMC26300S busulfan1954FDA S carboplatin1986ARMC22318S carmustine(BCNU)1977FDA S chlorambucil1956FDA S chlortrianisene pre-1981Boyd S

cis-diamminedichloroplatinum1979FDA S cyclophosphamide1957FDA S dacarbazine1975FDA S diethylstilbestrol pre-1970Cole S flutamide1983ARMC19318S fotemustine1989ARMC25313S heptaplatin/SK-2053R1999ARMC35348S hexamethylmelamine1979FDA S hydroxyurea1968FDA S ifosfamide1976FDA S levamisole pre-1981Boyd S lobaplatin1998DNP1235S lomustine(CCNU)1976FDA S lonidamine1987ARMC23337S mechlorethanamine1958FDA S melphalan1961FDA S miriplatin hydrate2010DNP2317S mitotane1970FDA S nedaplatin1995ARMC31347S nilutamide1987ARMC23338S nimustine hydrochloride pre-1981Boyd S oxaliplatin1996ARMC32313S pamidronate1987ARMC23326S pipobroman1966FDA S plerixafor hydrochloride2009DNP2217S porfimer sodium1993ARMC29343S procarbazine1969FDA S ranimustine1987ARMC23341S razoxane pre-1977Carter S semustine(MCCNU)pre-1977Carter S sobuzoxane1994ARMC30310S sorafenib2005DNP1945S thiotepa1959FDA S triethylenemelamine pre-1981Boyd S zoledronic acid2000DNP1424S alectinib hydrochloride2014DT51(1)56S/NM anastrozole1995ARMC31338S/NM apatinib mesylate2014DT51(1)56S/NM bicalutamide1995ARMC31338S/NM bortezomib2003ARMC39345S/NM camostat mesylate1985ARMC21325S/NM dasatinib2006DNP2027S/NM enzalutamide2012I438422S/NM erlotinib hydrochloride2004ARMC40454S/NM fadrozole HCl1995ARMC31342S/NM gefitinib2002ARMC38358S/NM imatinib mesilate2001DNP1538S/NM lapatinib ditosylate2007ARMC43475S/NM letrazole1996ARMC32311S/NM