Majority of Drug Discovery Investment Today Spent on Non Productive Projects

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Even modest systemic improvements in success rates at each of the stages have an enormous cumulative impact (Figure 11). By building a superior screening file we might conservatively expect to increase hit rates for leads from 25 to 50%. By starting with more leads from multiple chemotypes and by vortexing them using parallel optimization, there is every possibility of improving the lead to candidate development yield from 60 to 80%. The industry aggregate experience tells us that exploratory development success rates can rise sharply whenever we work with diverse families of leads. In addition, it is intrinsically obvious that this also creates a strong intellectual property estate and gives us flexibility and speed in reacting to clinical findings. As we build in a closed feedback loop between chemistry and biology and as we work within gene families, we can expect confidence in rational to rise - although that will come slowly and the impact will be modest and less certain early on. The consequence of the change in trajectory at the earliest stage in the discovery process would be a five fold increase in productivity.

Success Rates: The Opportunity

Ideas Leads Dev. Candidates Ph2a Clin. Products

Figure 11.

Ideas Leads Dev. Candidates Ph2a Clin. Products

Figure 11.

Conclusion: While the productivity of the biomedical enterprise has not yet met the rising expectations of our investors or of the patients and their families who need to see real advances in medicine, the technologies developed during the last two decades exist or can be adapted to make the required advances in the pace of new discovery. The key hurdle lies not with technology but with how we organize to implement new paradigms so as to challenge the fundamental statistics of the pharmaceutical R and D enterprise. To achieve this quantum jump in productivity will require the sort of management attention that normally is reserved for development candidates. It will require investment, alliances and most of all a change in both culture and organization. Strong chemistry leadership and a willingness to challenge existing conventions is required. It will undoubtedly also require creative investments in new people and technology, but to yield the increase in new product flow required to sustain the biomedical enterprise. The author believes that the answers are now palpable - in our technology and in our experiences - to discover and to experiment our way to the required advances. The penalty for not setting out to try is certain failure.

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Acknowledgements: The author would like to thank; Marty Haslanger (Amphora), Nick Saccomano (Pfizer), Alan Main (Lexicon Genetics), Steven Holtzman (Infinity Pharmaceuticals), Roger Longman (Windover), Colin Gardner (Transform), Richard DiMarchi (Lilly), Rod MacKenzie (Pfizer), Peter Hirth (Plexxion), Steve Kaldor (Syrrx) and Fred Vinick (Genzyme) for helpful and instructive discussions along the way.

COMPOUND NAME, CODE NUMBER AND SUBJECT INDEX, VOL. 38

ertapenem (MK-826), 186 (+)-febrifugine, 208 (+/-)-PHCCC, 24 (WHO) World Health Organisation, 375, 380

(WSSD) World Summit on sustainable Development, 381 [3H]-3-(methoxy methyl-3-[{2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 27 [3H]-3-methoxy-PEPy, 27 [3H]methoxymethyl-MTEP, 27 [3HJMK-801, 2 [3H]-M-MPEP, 27 [3H]SN003, 14 17AAG, 193, 194 17-DM AG, 194

2-Aminocyclohex-3-enecarboxylic acid, 163 2-PMPA, 3

4-substituted 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 165

5-aminosalicylate (5-ASA), 142,146, 148

5-ß-pregnane-3,20-dione, 318 5CITEP, 177

5'-OH nucleosides, 122

6-a-hydroxypaclitaxel, 341 6ß-hydroxycortisol, 323 9-cis-retinoic acid, 318 9H-xanthene-9-carbonyl)-carbamic acid butyl ester, 22

Ai / A2a / A2B subtypes, 127 Ai/A2a receptors, 121 A-217213 , 188 a2D adrenergic agonist, 339 As receptor, 121, 123, 124,127 A3 receptor structure, 122 A3 receptors, 122 A-317344, 7 A-317491, 7 A3-agonist, 123

A3-antagonists, 124,125,126,127, 128

abacavir, 257 abacavir (1592U89), 173 ABT-492 , 189 ABT-594, 7

ACH-126443 (elvucitabine), 214 actin cytoskeleton, 278 actos (pioglitazone), 72, 74 acyclovir, 342 acylation, 277 ADAM-17, 153 adefovir dipivoxil, 213 adenine derivatives, 127

adenosine, 121,124 adenosine A3-agonists, 122 adenosine antagonists, 127 adenosine receptor agonist, 338 adenosine receptor antagonist, 338 adenosine Receptors, 8,121 adipocyte, 72, 77 Adocia-sulfate-2 , 195 African trypanosomiasis, 379 AK-602, 179 Aldose reductase, 311 alicaforsen ISIS-2302, 143,147 allergic rhinitis, 131, 132,137 Alzheimers disease, 256 Alzheimer's disease, 41,42,43,44, 45, 46, 47 AM336, 4

amdoxivir (DAPD), 173 American trypanosomiasis, 379 aminopeptidases, 112 Amiodarone, 166 amodiaquine, 206 AMPA antagonist, 308 Amphotericin B, 167, 169 a-MSH, 31 Anandamide, 6 androstanol, 316 androstenol, 316

angiotensin converting enzyme, 112, 114

Anidulafungin, 169 antagonists, 77 antalarmin, 11 antibody, 132,229 antiinflammatory agents, 47 antipyrine, 323 Anti-viral response, 262 aP2, 77 apoCIII, 72 APOE4, 256

aprepitant (MK-869, L-754030, Emend), 11,12 arofylline, 145 arteether, 206 artemisinin, 206, 207 arteriosclerosis, 73 aryl hydrocarbon receptor (AhR), 316, 319, 321

aspartyl proteases, 42, 43,44, 45 asthma, 132 AT-130, 214

atazanavir (BMS-232632), 175 atorvastatin, 325 atovaquone, 208 attrition, 383, 384 Auristatin, 234

avandia (rosiglitazone), 72, 74 axokine, 242

AZ242 (Galida, tesaglitazar), 74 Azithromycin, 187 B cell receptor (BCR), 275 B1 antagonist, 114 B1 antagonists, 113,114,118 B1 receptor, 117 B1 receptor, 116 B1 receptors, 113,114 B2 receptor, 117 B2 receptor, 116

B2 receptor peptide antagonist, 113 BakBH3, 312

balaglitazone (NN 2344, DRF 2593), 74

balsalazide, 142,148 Bay 57-1293, 219 BAY36-7620, 24 Bay-41-4109, 214 ß-chemokine, 131 ß-chemokine ligands, 132 ß-chemokine receptor, 132 Bcl-2, 298,312 BcI-xl, 298, 312 benextramine, 67 benzo(a)pyrene, 321 benzofuran (RO-09-4609), 164 bezafibrate, 71 BILN-2061, 225 BILS-179 BS, 219 BIO-1211, 147

biopharmaceutical industry, 383 BIRB-796, 146 BIRT-377, 147 blockbusters, 383 BM13.1258 (R-483), 74 BM-17.0744, 73 BMS 298585, 75 BMS-193885, 65 BMS-433771, 221,222 BMS-561392, 159 BMS-806, 179 ß-naphthoflavone, 321 bradykinin, 112,112,113 bradykinin antagonists, 115 bradykinin B1 receptor, 111,113, 113,113

bradykinin B2 receptor, 111,113, 113

bradykinin receptor subtypes, 112 bradykinin receptors, 8,111 bronchial asthma, 131,137 bronchial aveolar lavage, 133 bronchial hyperesponsiveness, 136 bronchial hyperreactivity, 136

bronchoalveolar lavage, 131 budesonide, 142 BVT.142, 75 BW 4030W92, 5 Caco-2 cells, 322 caffeine, 319

Calcitonin gene-related peptide, 8 calcium-channel blockers, 327 Caleicheamicin, 231 calothrixin, 209 cAMP, 23

Cannabinoid receptor, 241 Cannabinoid Receptors, 8 capravine (AG1549,S-1153), 174 capromorelin, 86 Capsaicin, 6 CAR, 288

carbamazepine, 318, 323 Carbon dioxide, 376 carbonic anhydrase, 310 carboxylesterases, 317 cardioprotection, 124 carrageenan-induced hyperalgesia, 116

caspase-3, 312 caspase-9, 312 Caspofungin, 168 Catalyst, 305 Catalytic RNAs, 296 cathepsin B, 291 cathepsin D, 309 CCR1, 133 CCR2, 137

CCR3, 132,133, 133, 135, 136, 137 CCR3 antagonist, 132,335 CCR3 antagonists, 136,137 CCR3 p-chemokine agonists, 132 CCR3 binding, 134 CCR3 monoclonal, 132 CCR3 receptor, 136 CCR3 selectivity, 135 CCR5, 135,137 CDK-2, 305 cefditoren, 185 cefditoren pivoxil, 185 cefotiam, 185 ceftizoime alapivoxil, 185 ceftizoxime alapivoxil (CFX-AP, AS-924), 186

Cethromycin (ABT-773), 188 CGP 71683A, 11,15,65 CGP-51594, 2

chaperone protein hsp90, 319 chemical diversity, 384, 386 chemical genetics, 385 chemokine receptor CCR3, 137

chemokines, 131 chemotactic cytokines, 131 chemotaxis, 131,132,134 chem-X, 306 chloroquine, 205, 206, 209 cholecystokinin antagonists, 92, 96 cholecystokinin Receptors, 8 cholera, 378, 379 cholesterol, 275

chronic inflammatory diseases, 131

chronic inflammatory pain, 111,118

chymase inhibitors, 307

chymotrypsin, 297

cidofovir, 223

cilofungin, 164, 169

cilomilast, 145

cisapride, 89, 95

cispentacin, 163

CITCO, 319

CK-0106023, 196

CK-0238273, 196

Clevudine, 214

climate change, 375, 376, 376, 377,

clofibrate, 71

clotrimazole, 318

CNI-1493, 146

CNS5161, 2

CNVIIA, 4

combinatorial chemistry, 387 combinatorial libraries, 297, 298 computaional programs, 388 conjugate, 229 consensus scoring, 308 constitutive androstane receptor (CAR), 316,318,320,326 copegus, 215 coronavirus, 222 corticosterone, 318 cortistatin (CST), 86 coumestrol, 318 coviracii (Clevudine), 214 COX-1, 342 CP-101606, 3 CP-122721, 11,12 CP-154,526, 11 CP-661,631, 158 CP-671906, 64,65 CPCCOOEt, 24 CPPene, 2 CPPHA, 22 C-reactive protein, 72 CRF receptor antagonist, 11 CRF1 antagonist, 13, 14 CS-758 (R-120758), 167

CS-834 , 186 cyanovirin-N, 179

cyclin-dependent Kinase (CDK), 334

Cyclo-D4G, 173

cyclooxygenase-2 (COX-2), 342

cyclosporin, 325

CYP1A1, 319

CYP2B6, 317,319

CYP2C19, 317

CYP2C8, 317

CYP2C9, 317

CYP3A4, 317

CYP3A4 reporter gene assay, 323 Cytochrome P450, 297 Cytochrome P450 2D6, 256 DABP-GTP, 197 DAPIVIRINE (TMC-125), 174 darifenicin, 58 data mining, 384, 392 Dengue Fever, 378 Devazepide (L-364718), 92,96 dexamethasone, 318, 319 dexamethasone-t-butylacetate, 318, 320

dexloxiglumide, 92, 96

DFB, 22

DHFR, 305

diabetes, 99

diabetes mellitius, 256

Dicer, 263

digoxin, 324

DISCO, 305

disease genes, 385

disease Vectors, 376

diverse screening file, 387

diversity oriented synthesis (DOS),

DMP696, 11

DNAgyrase, 312

DNK333, 11,12

docetaxel, 320

DOCK, 308

dolastatin, 234

dopamine D2 agonist, 337

dopamine D3 receptor, 336

dopamine D4 receptor, 343

dopamine transporter, 306, 334

doxorubicin, 230, 234

DPC333, 159

DPC-083, 174

DPC-333 (BMS-561392), 144

DPC-681, 177

DPC-684, 177

DQ-113, 190

DRF 2593 (NN 2344, balaglitazone), 74

drought, 376

drug chemical space, 387

drug discovery invesment, 394

drug targeting, 229

drugability, 384, 389, 391

drugable lead, 390

drugScore, 311

duloxetine, 51,58

DW-286, 190

ecteinascidin, 318, 320

efavirenz, 174

eicosanoids, 72

eletriptan, 325

El-Nino, 378

elvucitabine, 214

EM574, 93

emtricitabine, 214

emtricitabine (TMC), 174

emvirine (MKC-422), 175

endothelial differentiation gene, 308

enfurvitide (T-20, pentafuside), 179

entecavir, 214

enzyme, structure-function, 42, 43, 44, 45

enzymes, proteolytic inhibition , 41, 42, 43, 44, 45, 46, 47 eosinophil leukocyte, 131 eosinophil recruitment, 137 eotaxin, 131, 132,132,136 eotaxin-2, 132 eotaxin-3, 132

eotaxin-induced Ca2+ flux, 137,137 eotaxin-induced Chemotaxis, 135, 136

erythromycin, 92 estrogen receptor, 309 etanercept, 143, 144 ethinylestradiol, 327 eupolauridine, 165 external weather events, 377 F-15784, 165 FAAR, 72 famine, 377

famesyltransferase, 339, 354 faropenem, 184,185 Fc receptor, 275 fenofibrate, 71 fexofenadine, 325 fibrates, 72 fibrinogen, 72

Flavin Mononucleotide Reductase domain (FMN domain), 297 flexX, 308 flooding, 378,380

Fluconazole (Diflucan), 166,167, 168, 169

Flucytosine, 170 fosamprenavir (GW433908), 177 FR252383, 11 FR252384, 14,66 FR901379, 168 fragment assembly, 300 FTIR, 297 FXR, 288

Gai2, Gai3, 197, 198 GABAa receptor, 334 Gabapentin, 4, 5 GAL4 transcription factor, 295 Galanin Receptors, 8 galida (tesaglitazar, AZ242), 74 ganciclovir, 342

ganefloxacin (BMS-284756) , 189 GASP, 305 gatifloxacin, 189 geldanamycin, 193 gemifloxacin , 189 gene families, 393, 394 gene silencing, 261 generalized anxiety disorder, 28 genome scan, 250 genome surveillance, 262 genomics, 383, 385, 392 ghrelin, 81, 82, 83, 84, 85, 86, 87 GHRP-2, 85 GHRP-6, 81,87 GL-047296, 164 GL-406349, 164 GL-663142, 164 glucocorticoid receptor (GR), 319 Glucocorticoids, 281 Glutamate Site Antagonists, 1 glutathiones-transferase, 317 Glycine Site Antagonists, 2 GOLD, 308

gonadotropin releasing hormone (GnRH), 337 GPCR, 306 GPCRs, 7,8,21,296 GPI-5232, 4

G-protein coupled receptor, 132 G-protein coupled receptors, 112 GRACE, 166 granisetran, 91,95 Greenhouse effect, 376 Greenhouse gases, 376 growth hormone secretagogue receptor (GHSRIa), 81, 82, 83, 84 GTPase, 196,197 GV-196771A, 2 GW3333, 156

GW-3333, 144 GW409544, 75 GW438014A, 67 GW-471552, 164 GW-471558, 164 GW501516, 75 GW9662, 77 halofantrine, 208 HBV, 213,214,342 HCMV, 218,219,220,342 HCV, 216,217,218 HCVE2, 217 HCV IRES, 217

HCV NS3 Serine Protease Inhibitor, 215,216

HCV NS5b Polymerase Inhibitor,

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