Joumnal of Natural Products Review ough discussi in Figure S. we have not found any clinical trials reported on these of modifications of natural con ories used nds that are as follows tantino ar NBNadcot(thav vileged st may b time often found by random ates In overview of Results.Th zed in and onsubdivisions,the reader should ture a the adw ent in 2001 o red is the 30 years from 01/01/1981 to 12/31/2010: New roved drugs:With all source categories By sou of th (ue siPTK hibitors rated in the 2003 and have (Figure 3) er direc nhibit rces f small-molecule NCEs:By source/year N/NB/ND:By year (Figure 5) and trade names, nply produced by synth nd trade names,year d gr up for and source (Table 4) luct mimi dd co nsult the wHh20o9 tive drugs:All molecules,source,and number nd Anticancer drugs:Generic and trade names,year, cs of the sin II stn ng AT /AT照 tL-162313(3 sartans)into the (a pep udot ides lified by 4.which is nt（binding n and has a betre ll ha ng as repor products and structures derived from or reated tonatur the develop dd/0,1021/mp20os11e2012.75.11-35
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. Nat. Prod. 2012, 75, 311−335
Journal of Natural Products Review Table 2.Antibacterial Drugs from 01/01/1981 to 12/31/2010 Organized Alphabetically by Generic Name within Source 98 298 003003000030景300000000000素KN景影影题0M0003030000000 z o201275,31-3g
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
Journal of Natural Product Table 2.continued 1iananaeil.beioi0 ACWY- 911202 A.TT le typhoid va Typheri ONP 12 35 of the educed level of products in spite 人ed2012.75311-35
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
lournal of Na Table 3 Antifungal drug 01/01/198 12/31/201 rate of NCE rial ch 13s e nto the ing the majority of the antitumo ed)in the pharma inue gents fall i he .S be t is to be pe ar 吧 tim 010 time ha 200 and the yea 270 (23.9%)of the total (3 f stry pr ling into
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