《天然药物化学》课程参考文献（天然药物研究与开发）Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010.pdf_大学文库

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010 David J. Newman* and Gordon M. Cragg Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute−Frederick, P.O. Box B, Frederick, Maryland 21702, United States *S Supporting Information ABSTRACT: This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74.8%, are other than “S” (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore we consider that this area of natural product research should be expanded significantly. ■ INTRODUCTION It has been 14 years since the publication of our first,1 eight years since the second,2 and four years3 since our last full analysis of the sources of new and approved drugs for the treatment of human diseases, although there have been intermediate reports in specific areas such as cancer4,5 and anti-infectives,6 together with a more general discussion on natural products as leads to potential drugs.7 All of these articles demonstrated that natural product and/or natural product structures continued to play a highly significant role in the drug discovery and development process. That Nature in one guise or another has continued to influence the design of small molecules is shown by inspection of the information given below, where with the advantage of now 30 years of data, the system has been able to be refined. We have eliminated some duplicated entries that crept into the original data sets and have revised a few source designations as newer information has been obtained from diverse sources. In particular, as behooves authors from the National Cancer Institute (NCI), in the specific case of cancer treatments, we have continued to consult the records of the FDA and added comments from investigators who have informed us of compounds that may have been approved in other countries and that were not captured 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 30 years will be included in the data sets used in the overall discussion. A trend was mentioned in our 2003 review2 in that, though the development of high-throughput screens based on molecular targets had led to a demand for the generation of large libraries of compounds, the shift away from large combinatorial libraries that was becoming obvious at that time has continued, with the emphasis now being on small focused (100 to ∼3000 plus) collections that contain much of the “structural aspects” of natural products. Various names have been given to this process, including “diversity oriented syntheses”, 8−12 but we prefer to simply refer to “more natural product-like”, in terms of their combinations of heteroatoms and significant numbers of chiral centers within a single molecule,13 or even ”natural product mimics” if they happen to be direct competitive inhibitors of the natural substrate. It should also be pointed out that Lipinski's fifth rule effectively Special Issue: Special Issue in Honor of Gordon M. Cragg Received: November 14, 2011 Published: February 8, 2012 Review pubs.acs.org/jnp This article not subject to U.S. Copyright. Published 2012 by the American Chemical Society 311 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

states that the first 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”. 14−16 Recent commentaries on the “industrial perspective in regard to drug sources” 17 and high-throughput screening18 have been published by the GSK group and can be accessed by interested readers. Although combinatorial chemistry in one or more of its manifestations has now been used as a discovery source for approximately 70% of the time covered by this review, to date, we still can find only one de novo new chemical entity reported in the public domain as resulting from this method of chemical discovery and approved for drug use anywhere. This is the antitumor compound known as sorafenib (Nexavar, 1) from Bayer, approved by the FDA in 2005 for treatment of renal cell carcinoma, and then in 2007, another approval was given for treatment of hepatocellular carcinoma. It was known during development as BAY-43-9006 and is a multikinase inhibitor, targeting several serine/threonine and receptor tyrosine kinases (RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3). It has been approved in Switzerland, the European Union, and the People’s Republic of China, with additional filings in other countries. Currently, it is still in multiple clinical trials in both combination and single-agent therapies, a common practice once a drug is approved for an initial class of cancer treatment. As mentioned by the present authors and others in prior reviews on this topic, the developmental capability of combinatorial chemistry as a means for structural optimization, once an active skeleton has been identified, is without par. An expected surge in productivity, however, has not materialized. 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 of 25 in 2004 (although 28% of these were assigned to the “ND” category), leading to a rebound to 54 in 2005, with 24% being “N” or “ND” and 37% being biologics (“B”) or vaccines (“V”), as we discuss subsequently. The trend to small numbers of approvals continues to this day, as can be seen by inspection of Figures 2 and 4 (see Discussion section below). Fortunately, however, research being conducted by groups such as Danishefsky’s, Ganesan’s, Nicolaou’s, Porco’s, Quinn’s, Schreiber’s, Shair’s, Tan’s, Waldmann’s, and Wipf’s, together with those of other synthetic chemists, is continuing the modification of active natural product skeletons as leads to novel agents. This was recently exemplified by the groups of Quinn19 and Danishefsky20 or the utilization of the “lessons learned” from studying such agents as reported by the groups of Tan21,22 and Kombarov23 to name just some of the recent publications. Thus, in due course, the numbers of materials developed by linking Mother Nature to combinatorial synthetic techniques should increase. These aspects, plus the potential contributions from the utilization of genetic analyses of microbes, will be discussed at the end of this review. 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 1981 through December 2010. As in our earlier analyses,1−3 we have consulted the Annual Reports of Medicinal Chemistry, in this case from 1984 to 2010,24−50 and have produced a more comprehensive coverage of the 1981−2010 time frame through addition of data from the publication Drug News and Perspective51−71 and searches of the Prous (now ThomsonReuter’s Integrity) database, as well as by including information from individual investigators. As in the last review, biologics data prior to 2005 were updated using information culled from Figure 1. All new approved drugs. Journal of Natural Products Review 312 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

disparate sources that culminated in a 2005 review on biopharmaceutical drugs.72 We have also attempted to capture vaccine data in the past few years, but this area of the database is not as complete as we would hope. We have also included relevant references in a condensed form in Tables 2−5 and 8−10. If we were to provide the 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. Similarly, “DNP ##” refers to the volume of Drug News and Perspective and the corresponding page(s), though this journal has now ceased publication as of the 2010 volume, and an “I ######” is the accession number in the Prous (now Thomson-Reuters, Integrity) database. Finally, we have used “Boyd” to refer to a review article73 on clinical antitumor agents and “M’dale” to refer to Martindale74 with the relevant page noted. It should be noted that the “year” header in all tables is equivalent to the “year of introduction” of the drug. In a number of cases over the years, there are discrepancies between sources as to the actual year due to differences in definitions. Some reports will use the year of approval (registration by nonUSA/FDA organizations), while others will use the first recorded sales. We have generally taken the earliest year in the absence of further information. ■ RESULTS As in previous reviews, we have covered only new chemical entities in the present analysis. As mentioned in the earlier reviews, if one reads the FDA and PhRMA Web sites, the numbers of NDA approvals are in the high ten to low hundred numbers for the past few years. If, however, combinations of Figure 2. All new approved drugs by source/year. Figure 3. Source of small-molecule approved drugs. Journal of Natural Products Review 313 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

older drugs and old drugs with new indications and/or improved delivery systems are removed, then the number of true NCEs has ranged between the 20s to just over 50 per year since 1989. If one now removes biologicals and vaccines, thus noting only “small molecules”, then the figures show that over the same time frame the numbers have been close to 40 for most of the 1989 to 2000 time frame, dropping to 20 or less from 2001 to 2010 with the exception of 2002 and 2004, when the figures climbed above 30 (cf. Figures 2 and 4). For the first time, now with 30 years of data to analyze, it was decided to add two other graphs to the listings, of which one might be of significant interest to the natural products community. In Figure 5 the percentages of approved NCEs have been plotted per year from 1981 to 2010, where the designation is basically an “N” or a subdivision (“NB” or “ND”) with the total numbers of small molecules approved by year as a point chart in Figure 6. Thus, we have deliberately not included any designations that could be considered as “inspired by a natural product structure”, although from the data provided Table 1. continued indication total B N NB ND S S/NM S* S*/NM V bronchodilator 8 2 6 calcium metabolism 20 8 9 3 cardiotonic 13 3 2 3 5 chelator 4 4 contraception 9 8 1 diuretic 6 4 2 erythropoiesis 5 5 gastroprokinetic 4 1 2 1 hematopoiesis 6 6 hemophilia 12 12 hormone 22 12 10 hormone replacement therapy 8 8 hypnotic 12 12 hypocholesterolemic 13 4 1 2 1 5 hypolipidemic 8 1 7 immunomodulator 4 2 1 1 immunostimulant 11 5 3 2 1 immunosuppressant 12 4 5 3 irritable bowel syndrome 4 1 3 male sexual dysfunction 4 4 multiple sclerosis 6 3 1 1 1 muscle relaxant 10 4 2 1 3 neuroleptic 9 1 6 2 nootropic 8 3 5 osteoporosis 5 3 1 1 platelet aggregation inhibitor 4 3 1 respiratory distress syndrome 6 3 1 1 1 urinary incontinence 5 2 3 vulnerary 5 2 2 1 Grand Total 1130 144 47 3 247 325 130 50 116 68 a Diseases where ≤3 drugs approved 1981−2010; 225 drugs fall into this category and are subdivided as follows: B, 58; N, 12; NB, 2; ND, 52; S, 62, S/NM. 16; S*, 5; S*/NM, 6; V, 12. The diseases covered the following; 5 α-reductase inhibitor, ADHD, CAPS, CHF, CNS stimulant, Crohn’s disease, DVT, Fabry’s disease, Gaucher’s disease, Hunter syndrome, Japanese encephalitis, Lambert-Eaton myasthenic syndrome, Lyme disease, MI acute, MMRC, PAH, PCP/toxoplasmosis, PNH, Pompe’s disease, Turner syndrome, abortifacient, acromelagy, actinic keratoses, adjuvant/colorectal cancer, alcohol deterrent, allergic rhinitis, anabolic metabolism, analeptic, anemia, anti sickle cell anemia, antismoking, antiacne, antiathersclerotic, anticonvulsant, antidiarrheal, antidote, antiemphysemic, antihyperuricemia, antihypotensive, antinarcolepsy, antinarcotic, antinauseant, antiperistaltic, antipneumococcal, antiprogestogenic, antirheumatic, antisecretory, antisepsis, antiseptic, antispasmodic, antispastic, antitussive, antityrosinaemia, antixerostomia, atrial fibrillation, benzodiazepine antagonist, β-lactamase inhibitor, blepharospasm, bone disorders, bone morphogenesis, bowel evacuant, cardioprotective, cardiovascular disease, cartilage disorders, cervical dystonia, choleretic, chronic idiopathic constipation, cognition enhancer, congestive heart failure, constipation, cystic fibrosis, cytoprotective, dementia (Alzheimer’s), diabetic foot ulcers, diabetic neuropathies, digoxin toxicity, dpt, dry eye syndrome, dyslipidemia, dysuria, endometriosis, enzyme, expectorant, fertility inducer, gastroprotectant, genital warts, hematological, hemorrhage, hemostasis, hemostatic, hepatoprotectant, hereditary angioedema, homocystinuria, hyperammonemia, hyperparathyroidism, hyperphenylalaninemia, hyperphosphatemia, hyperuricemia, hypoammonuric, hypocalciuric, hypogonadism, hyponatremia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, immediate allergy, infertility (female), inflammatory bowel disease, insomnia, joint lubricant, lipoprotein disorders, macular degeneration, mucolytic, mucopolysaccharidosis, mucositis, myleodysplasia, narcolepsy, nasal decongestant, neuropathic pain, neuroprotective, ocular inflammation, opiate detoxification, osteoarthritis, overactive bladder, ovulation, pancreatic disorders, pancreatitis, pertussis, photosensitizer, pituitary disorders, porphyria, premature birth, premature ejaculation, progestogen, psychostimulant, pulmonary arterial hypertension, purpura fulminans, rattlesnake antivenom, reproduction, restenosis, schizophrenia, sclerosant, secondary hyperthryoidism, sedative, skin photodamage, strabismus, subarachnoid hemorrhage, thrombocytopenia, GH deficiency, ulcerative colitis, urea cycle disorders, uremic pruritis, urolithiasis, vaccinia complications, varicella (chicken pox), vasodilator, vasodilator (cerebral), vasodilator (coronary), vasoprotective, venous thromboembolism. Journal of Natural Products Review 315 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

either in the tables or from the Supporting Information any reader who so desires may calculate their own particular variation(s) in Figure 5. As in our earlier reviews,1−3 the data have been analyzed in terms of numbers and classified 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 (>45 residues) peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host. “N” Natural product. “NB” Natural product “Botanical” (in general these have been recently approved). “ND” Derived from a natural product and is usually a semisynthetic modification. “S” Totally synthetic drug, often found by random screening/modification 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). (For amplification of the rationales used for categorizing using the above subdivisions, the reader should consult the earlier reviews.1−3 ) In the field of anticancer therapy, the advent in 2001 of Gleevec, a protein tyrosine kinase inhibitor, was justly heralded as a breakthrough in the treatment of leukemia. This compound was classified as an “/NM” on the basis of its competitive displacement of the natural substrate, ATP, in which the intracellular concentrations can approach 5 mM. We have continued to classify PTK and other kinase inhibitors that are approved as drugs under the “/NM” category for exactly the same reasons as elaborated in the 2003 review2 and have continued to extend it 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 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. In addition, 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. For further information on this area, interested readers should consult the excellent earlier review by Hruby,75 his 2009 “Perspective” review,76 and very recent work in the same area by Audie and Boyd77 and VanHee et al.78 in order to fully appreciate the potential of such (bio)chemistry. As an example of what can be found by studies on relatively simple peptidomimics of the angiotensin II structure, the paper of Wan et al.79 demonstrating the modification of the known but nonselective AT1/AT2 agonist L-162313 (2, itself related to the sartans) into the highly selective AT2 agonist 3 (a peptidomimetic structure) led to the identification of short pseudopeptides exemplified by 4, which is equipotent (binding affinity = 500 pM) to angiotensin II and has a better than 20 000-fold selectivity versus AT1, whereas angiotensin II has only a 5-fold binding selectivity in the same assay,80 as reported in our 2007 review. The chemistry leading to these compounds was reported in 2007 in greater detail by Georgsson et al.,81 with a thorough discussion of the role of AT2 receptors in a multiplicity of disease states being published in 2008.82 To date, we have not found any clinical trials reported on these materials. In the area of modifications of natural products by combinatorial methods to produce entirely different compounds that may bear little if any resemblance to the original, but are legitimately assignable to the “/NM” category, citations are given in previous reviews.8,83−90 In addition, one should consult the reports from Waldmann’s group91,92 and those by Ganesan,93,94 Shang and Tan,95 Bauer et al.,21 Constantino and Barlocco,96 Bade et al.,97 and Violette et al.,98 demonstrating the use of privileged structures as a source of molecular skeletons around which one may build libraries. Another paper of interest in this regard is the editorial by Macarron from GSK,15 as this may be the first time where data from industry on the results of HTS screens of combichem libraries versus potential targets were reported with a discussion of lead discovery rates. In this paper, Macarron re-emphasizes the fifth Lipinski rule, which is often ignored: “natural products do not obey the other four”. Overview of Results. The data we have 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 the 30 years from 01/01/1981 to 12/31/2010: New approved drugs: With all source categories (Figure 1) New approved drugs: By source/year (Figure 2) Sources of all NCEs: Where four or more drugs were approved per medical indication (Table 1), with listings of diseases with ≤3 approved drugs Sources of small-molecule NCEs: All subdivisions (Figure 3) Sources of small-molecule NCEs: By source/year (Figure 4) Percent N/NB/ND: By year (Figure 5) Total small molecules: By year (Figure 6) Antibacterial drugs: Generic and trade names, year, reference, and source (Table 2) Antifungal drugs: Generic and trade names, year, reference, and source (Table 3) Antiviral drugs: Generic and trade names, year, reference, and source (Table 4) Antiparasitic drugs: Generic and trade names, year, reference, and source (Table 5) Anti-infective drugs: All molecules, source, and numbers (Table 6) Anti-infective drugs: Small molecules, source, and numbers (Table 7) Anticancer drugs: Generic and trade names, year, reference, and source (Table 8; Figure 7) All anticancer drugs (very late 1930s−12/2010): Generic and trade names, year, reference, and source (Table 9; Figures 8, 9) Antidiabetic drugs: Generic and trade names, year, reference, and source (Table 10) The extensive data sets shown in the figures and tables referred to above 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 Journal of Natural Products Review 316 dx.doi.org/10.1021/np200906s | J. 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Table 2. Antibacterial Drugs from 01/01/1981 to 12/31/2010 Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source carumonam Amasulin 1988 ARMC 24 298 N daptomycin Cubicin 2003 ARMC 39 347 N fosfomycin trometamol Monuril 1988 I 112334 N isepamicin Isepacin 1988 ARMC 24 305 N micronomicin sulfate Sagamicin 1982 P091082 N miokamycin Miocamycin 1985 ARMC 21 329 N mupirocin Bactroban 1985 ARMC 21 330 N netilimicin sulfate Netromicine 1981 I 070366 N RV-11 Zalig 1989 ARMC 25 318 N teicoplanin Targocid 1988 ARMC 24 311 N apalcillin sodium Lumota 1982 I 091130 ND arbekacin Habekacin 1990 ARMC 26 298 ND aspoxicillin Doyle 1987 ARMC 23 328 ND astromycin sulfate Fortimicin 1985 ARMC 21 324 ND azithromycin Sunamed 1988 ARMC 24 298 ND aztreonam Azactam 1984 ARMC 20 315 ND biapenem Omegacin 2002 ARMC 38 351 ND cefbuperazone sodium Tomiporan 1985 ARMC 21 325 ND cefcapene pivoxil Flomox 1997 ARMC 33 330 ND cefdinir Cefzon 1991 ARMC 27 323 ND cefditoren pivoxil Meiact 1994 ARMC 30 297 ND cefepime Maxipime 1993 ARMC 29 334 ND cefetamet pivoxil HCl Globocef 1992 ARMC 28 327 ND cefixime Cefspan 1987 ARMC 23 329 ND cefmenoxime HCl Tacef 1983 ARMC 19 316 ND cefminox sodium Meicelin 1987 ARMC 23 330 ND cefodizime sodium Neucef 1990 ARMC 26 300 ND cefonicid sodium Monocid 1984 ARMC 20 316 ND cefoperazone sodium Cefobis 1981 I 127130 ND ceforanide Precef 1984 ARMC 20 317 ND cefoselis Wincef 1998 ARMC 34 319 ND cefotetan disodium Yamatetan 1984 ARMC 20 317 ND cefotiam HCl Pansporin 1981 I 091106 ND cefozopran HCl Firstcin 1995 ARMC 31 339 ND cefpimizole Ajicef 1987 ARMC 23 330 ND cefpiramide sodium Sepatren 1985 ARMC 21 325 ND cefpirome sulfate Cefrom 1992 ARMC 28 328 ND cefpodoxime proxetil Banan 1989 ARMC 25 310 ND cefprozil Cefzil 1992 ARMC 28 328 ND cefsoludin sodium Takesulin 1981 I 091108 ND ceftazidime Fortam 1983 ARMC 19 316 ND cefteram pivoxil Tomiron 1987 ARMC 23 330 ND ceftibuten Seftem 1992 ARMC 28 329 ND ceftizoxime sodium Epocelin 1982 I 070260 ND ceftobiprole medocaril Zeftera 2008 ARMC 44 589 ND ceftriaxone sodium Rocephin 1982 I 091136 ND cefuroxime axetil Zinnat 1987 ARMC 23 331 ND cefuzonam sodium Cosmosin 1987 ARMC 23 331 ND clarithromycin Klaricid 1990 ARMC 26 302 ND dalfopristin Synercid 1999 ARMC 35 338 ND dirithromycin Nortron 1993 ARMC 29 336 ND doripenem Finibax 2005 DNP 19 42 ND ertapenem sodium Invanz 2002 ARMC 38 353 ND erythromycin acistrate Erasis 1988 ARMC 24 301 ND flomoxef sodium Flumarin 1988 ARMC 24 302 ND flurithromycin ethylsuccinate Ritro 1997 ARMC 33 333 ND fropenam Farom 1997 ARMC 33 334 ND imipenem/cilastatin Zienam 1985 ARMC 21 328 ND lenampicillin HCI Varacillin 1987 ARMC 23 336 ND loracarbef Lorabid 1992 ARMC 28 333 ND meropenem Merrem 1994 ARMC 30 303 ND Journal of Natural Products Review 317 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

the physician. Inspection of the data shows the continued important role for natural products in spite of the current greatly reduced level of natural products-based drug discovery programs in major pharmaceutical houses. Table 2. continued generic name trade name year introduced volume page source moxalactam disodium Shiomarin 1982 I 070301 ND panipenem/betamipron Carbenin 1994 ARMC 30 305 ND quinupristin Synercid 1999 ARMC 35 338 ND retapamulin Altabax 2007 ARMC 43 486 ND rifabutin Mycobutin 1992 ARMC 28 335 ND rifamixin Normix 1987 ARMC 23 341 ND rifapentine Rifampin 1988 ARMC 24 310 ND rifaximin Rifacol 1985 ARMC 21 332 ND rokitamycin Ricamycin 1986 ARMC 22 325 ND roxithromycin Rulid 1987 ARMC 23 342 ND sultamycillin tosylate Unasyn 1987 ARMC 23 343 ND tazobactam sodium Tazocillin 1992 ARMC 28 336 ND telavancin HCl Vibativ 2009 DNP 23 15 ND telithromycin Ketek 2001 DNP 15 35 ND temocillin disodium Temopen 1984 ARMC 20 323 ND tigecycline Tygacil 2005 DNP 19 42 ND balafloxacin Q-Roxin 2002 ARMC 38 351 S besifloxacin Besivance 2009 DNP 23 20 S ciprofloxacin Ciprobay 1986 ARMC 22 318 S enoxacin Flumark 1986 ARMC 22 320 S fleroxacin Quinodis 1992 ARMC 28 331 S garenoxacin Geninax 2007 ARMC 43 471 S gatilfloxacin Tequin 1999 ARMC 35 340 S gemifloxacin mesilate Factive 2003 ARMC 40 458 S grepafloxacin Vaxor 1997 DNP 11 23 S levofloxacin Floxacin 1993 ARMC 29 340 S linezolid Zyvox 2000 DNP 14 21 S lomefloxacin Uniquin 1989 ARMC 25 315 S moxifloxacin HCl Avelox 1999 ARMC 35 343 S nadifloxacin Acuatim 1993 ARMC 29 340 S norfloxacin Noroxin 1983 ARMC 19 322 S ofloxacin Tarivid 1985 ARMC 21 331 S pazufloxacin Pasil 2002 ARMC 38 364 S pefloxacin mesylate Perflacine 1985 ARMC 21 331 S prulifloxacin Sword 2002 ARMC 38 366 S rufloxacin hydrochloride Qari 1992 ARMC 28 335 S sitafloxacin hydrate Gracevit 2008 DNP 22 15 S sparfloxacin Spara 1993 ARMC 29 345 S taurolidine Taurolin 1988 I 107771 S temafloxacin hydrochloride Temac 1991 ARMC 27 334 S tosufloxacin Ozex 1990 ARMC 26 310 S trovafloxacin mesylate Trovan 1998 ARMC 34 332 S brodimoprin Hyprim 1993 ARMC 29 333 S*/NM ACWY meningoccal PS vaccine Mencevax 1981 I 420128 V DTPw-HepB-Hib Quinvaxem 2006 DNP 20 26 V H. influenzae b vaccine Hibtitek 1989 DNP 03 24 V H. influenzae b vaccine Prohibit 1989 DNP 03 24 V MCV-4 Menactra 2005 DNP 19 43 V menACWY-CRM Menveo 2010 I 341212 V meningitis b vaccine MeNZB 2004 DNP 18 29 V meningococcal vaccine Menigetec 1999 DNP 14 22 V meningococcal vaccine NeisVac-C 2000 DNP 14 22 V meningococcal vaccine Menjugate 2000 DNP 14 22 V oral cholera vaccine Orochol 1994 DNP 08 30 V pneumococcal vaccine Prevnar 2000 DNP 14 22 V PsA-TT MenAfriVac 2010 I 437718 V vi polysaccharide typhoid vaccine Typherix 1998 DNP 12 35 V Journal of Natural Products Review 318 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

Inspection of the rate of NCE approvals as shown in Figures 2 and 4−6 demonstrates that, even in 2010, the natural products field is still producing or is involved in ca. 50% of all small molecules in the years 2000−2010. This is readily demonstrated in Figures 5 and 6, where the percentage of just the “N” linked materials is shown, with figures ranging from a low of 20.8% in 2009 to a high of 50% in 2010, with the mean and standard deviation for those 11 years being 36.5 ± 8.6, without including any of the natural product-inspired classifications (S*, S*/NM, and S/NM). What is quite fascinating is that in 2010 fully half of the 20 approved small-molecule NCEs fell into the “N” categories, including the majority of the antitumor agents (cf. Tables 2−4; 8). As was shown in the 2007 review, a significant number of all NCEs still fall into the categories of biological (“B”) or vaccines (“V”), with 282 of 1355 (or 20.8%) over the full 30-year period, and it is to be admitted that not all of the vaccines approved in these 30 years have been identified, although in the last 10 or 11 years probably a great majority have been captured. Thus, the proportion of approved vaccines may well be higher over the longer time frame. Inspection of Figure 2 shows the significant proportion that these two categories hold in the number of approved drugs from 2000, where, in some years, these categories accounted for ca. 50% of all approvals. If the three “N” categories are included, then the proportions of nonsynthetics are even higher for these years. This is so in spite of many years of work by the pharmaceutical industry devoted to high-throughput screening of predominately combinatorial chemistry products, and this time period should have provided a sufficient time span for combinatorial chemistry work from the late 1980s onward to have produced a number of approved NCEs. Overall, of the 1355 NCEs covering all diseases/countries/ sources in the years 01/1981−12/2010, and using the “NM” classifications introduced in our 2003 review,2 29% were synthetic in origin, thus demonstrating the influence of “other than formal synthetics” on drug discovery and approval (Figure 1). In the 2007 review, the corresponding figure was 30%.3 Inspection of Table 1 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, and inflammation, all with over 50 approved drug therapies. It should be noted, however, that numbers of approved drugs/disease do not correlate with the “value” as measured by sales. For example, the best selling drug of all is atorvastatin (Lipitor), a hypocholesterolemic descended directly from a microbial natural product, which sold over $11 billion in 2004, and, if one includes sales by Pfizer and Astellas Pharma over the 2004 to 2010 time frames, sales have hovered at $12−14 billion depending upon the year. The first U.S. patent for this drug expired in March 2010, and Ranbaxy, the Indian generics company, launched the generic version in the U.S. in December 2011, following FDA approval on the last day of the Pfizer patent, November 30, 2011. The major category by far is that of anti-infectives including antiviral vaccines, with 270 (23.9%) of the total (1130 for indications ≥ 4) falling into this one major human disease area. Table 3. Antifungal Drugs from 01/01/1981 to 12/31/2010 Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source interferon γ-n1 OGamma100 1996 DNP 10 13 B anidulafungin Eraxis 2006 DNP 20 24 ND caspofungin acetate Cancidas 2001 DNP 15 36 ND micafungin sodium Fungard 2002 ARMC 38 360 ND amorolfine hydrochloride Loceryl 1991 ARMC 27 322 S butoconazole Femstat 1986 ARMC 22 318 S ciclopirox olamine Loprox 1982 I 070449 S cloconazole HCI Pilzcin 1986 ARMC 22 318 S eberconazole Ebernet 2005 DNP 19 42 S fenticonazole nitrate Lomexin 1987 ARMC 23 334 S fluconazole Diflucan 1988 ARMC 24 303 S flutrimazole Micetal 1995 ARMC 31 343 S fosfluconazole Prodif 2003 DNP 17 49 S itraconazole Sporanox 1988 ARMC 24 305 S ketoconazole Nizoral 1981 I 116505 S lanoconazole Astat 1994 ARMC 30 302 S luliconazole Lulicon 2005 DNP 19 42 S naftifine HCI Exoderil 1984 ARMC 20 321 S neticonazole HCI Atolant 1993 ARMC 29 341 S oxiconazole nitrate Oceral 1983 ARMC 19 322 S posaconazole Noxafil 2005 DNP 19 42 S sertaconazole nitrate Dermofix 1992 ARMC 28 336 S sulconazole nitrate Exelderm 1985 ARMC 21 332 S terconazole Gyno-Terazol 1983 ARMC 19 324 S tioconazole Trosyl 1983 ARMC 19 324 S voriconazole Vfend 2002 ARMC 38 370 S butenafine hydrochloride Mentax 1992 ARMC 28 327 S/NM liranaftate Zefnart 2000 DNP 14 21 S/NM terbinafine hydrochloride Lamisil 1991 ARMC 27 334 S/NM Journal of Natural Products Review 319 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335

Table 4. Antiviral Drugs from 01.01.81 to 12.31.10 Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source interferon α Alfaferone 1987 I 215443 B interferon α-n3 Alferon N 1990 DNP 04 104 B interferon β Frone 1985 I115091 B immunoglobulin intravenous Gammagard Liquid 2005 I 231564 B interferon alfacon-1 Infergen 1997 ARMC 33 336 B IGIV-HB Niuliva 2009 DNP 23 16 B Oralgen 2007 I 415378 B peginterferon α-2a Pegasys 2001 DNP 15 34 B peginterferon α-2b Pegintron 2000 DNP 14 18 B resp syncytial virus IG RespiGam 1996 DNP 10 11 B palivizumab Synagis 1998 DNP 12 33 B interferon α-2b Viraferon 1985 I 165805 B interferon α-n1 Wellferon 1986 I 125561 B thymalfasin Zadaxin 1996 DNP 10 11 B enfuvirtide Fuzeon 2003 ARMC 39 350 ND laninamivir octanoate Inavir 2010 I 340894 ND peramivir PeramiFlu 2010 I 273549 ND zanamivir Relenza 1999 ARMC 35 352 ND imiquimod Aldara 1997 ARMC 33 335 S maraviroc Celsentri 2007 ARMC 43 478 S foscarnet sodium Foscavir 1989 ARMC 25 313 S raltegravir potassium Isentress 2007 ARMC 43 484 S delavirdine mesylate Rescriptor 1997 ARMC 33 331 S rimantadine HCI Roflual 1987 ARMC 23 342 S propagermanium Serosion 1994 ARMC 30 308 S efavirenz Sustiva 1998 ARMC 34 321 S nevirapine Viramune 1996 ARMC 32 313 S darunavir Prezista 2006 DNP 20 25 S/NM oseltamivir Tamiflu 1999 ARMC 35 346 S/NM entecavir Baraclude 2005 DNP 19 39 S* ganciclovir Cymevene 1988 ARMC 24 303 S* emtricitabine Emtriva 2003 ARMC 39 350 S* lamivudine Epivir 1995 ARMC 31 345 S* famciclovir Famvir 1994 ARMC 30 300 S* adefovir dipivoxil Hepsera 2002 ARMC 38 348 S* epervudine Hevizos 1988 I 157373 S* zalcitabine Hivid 1992 ARMC 28 338 S* inosine pranobex Imunovir 1981 I 277341 S* etravirine Intelence 2008 DNP 22 15 S* clevudine Levovir 2007 ARMC 43 466 S* zidovudine Retrovir 1987 ARMC 23 345 S* telbividine Sebivo 2006 DNP 20 22 S* sorivudine Usevir 1993 ARMC 29 345 S* valganciclovir Valcyte 2001 DNP 15 36 S* valaciclovir HCl Valtrex 1995 ARMC 31 352 S* penciclovir Vectavir 1996 ARMC 32 314 S* didanosine Videx 1991 ARMC 27 326 S* tenofovir disoproxil fumarate Viread 2001 DNP 15 37 S* cidofovir Vistide 1996 ARMC 32 306 S* stavudine Zerit 1994 ARMC 30 311 S* abacavir sulfate Ziagen 1999 ARMC 35 333 S* acyclovir Zovirax 1981 I 091119 S* amprenavir Agenerase 1999 ARMC 35 334 S*/NM tipranavir Aptivus 2005 DNP 19 42 S*/NM indinavir sulfate Crixivan 1996 ARMC 32 310 S*/NM saquinavir mesylate Invirase 1995 ARMC 31 349 S*/NM lopinavir Kaletra 2000 ARMC 36 310 S*/NM fosamprenevir Lexiva 2003 ARMC 39 353 S*/NM ritonavir Norvir 1996 ARMC 32 317 S*/NM atazanavir Reyataz 2003 ARMC 39 342 S*/NM neflinavir mesylate Viracept 1997 ARMC 33 340 S*/NM Journal of Natural Products Review 320 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335