Lead generation: methods, strategies, and case studies
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| Format: | Buch |
| Sprache: | English |
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Weinheim
Wiley-VCH Verlag GmbH & Co. KGaA
[2016]
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| Schriftenreihe: | Methods and principles in medicinal chemistry
volume 68 |
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| 245 | 1 | 0 | |a Lead generation |b methods, strategies, and case studies |c edited by Jörg Holenz |
| 264 | 1 | |a Weinheim |b Wiley-VCH Verlag GmbH & Co. KGaA |c [2016] | |
| 264 | 4 | |c © 2016 | |
| 300 | |a 2 Bände | ||
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| 337 | |b n |2 rdamedia | ||
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CONTENTS
DEDICATION V
UST OF CONTRIBUTORS XXI
PREFACE XXVII
A PERSONAL FOREWORD XXXI
VOLUME 68A
PART
YY
INTRODUCTION TO LEAD GENERATION 1
YY INTRODUCTION: LEARNINGS FROM THE PAST - CHARACTERISTICS OF
SUCCESSFUL LEADS 3
I
YY
A
YYYY
KE YYYYYYYY
ACKNOWLEDGMENTS 10
REFERENCES 10
2 MODERN LEAD GENERATION STRATEGIES 13
JOERG HOLENZ AND DEAN G. BROWN
2.1 LEAD GENERATION GREATLY INFLUENCES CLINICAL CANDIDATE QUALITY 14
2.2 SCREENING OT COMPOUND LIBRARIES HAS UNDERGONE A MAJOR PARADIGM
CHANGE IS
2.3 NEW CHEMICAL MODALITIES ARE AVAILABLE TO TACKLE DIFFICULT TARGETS IS
2.4 AS DEMANDS HAVE INCREASED
YY
NEW LEAD GENERATION METHODS EMERGED 16
2.5 HOW DO LEAD GENERATION CHEMISTS MEET THESE CHALLENGES AND
SUBSEQUENTLY PROVIDE SHEIR LEAD OPTIMIZATION COLLEAGUES WITH
HIGH_QUALITY LEAD SERIES? 17
2.5.1 LEARNINGS CAN BE DRAWN FROM LG PROJECT FAILURES 17
2.5.2 HOW MANY COMPOUNDS TO SCREEN TO GENERATE HIGH-QUALITY LEADS? 18
2.5.3 WHICH COMPOUNDS TO SCREEN TO GENERATE HIGH-QUALITY LEADS? 19
2.5.4 DEVELOPING PROJECT-CUSTOMIZED, CONCERTED, AND COMPEHENSIVE LEAD
GENERATION STRATEGIES WILL INCREASE LG SUCCESS RATES: THE CREATION
OF LEADS 20
2.5.5 SELECTING THE TARGET DEFINES LG SUCCESS RATES 21
2.5.6 LEAD GENERATION SHOULD BE COMPLEMENTED BY AUXILIA
YY
TECHNOLOGIES
TO CHARACTERIZE HITS 21
2.5.7 PHENOTYPIC SCREENS ARE OFTEN COMPLEMENTED BY A CHEMICAL BIOLOGY
ARM 22
2.5.8 THE LEAD GENERATION STRATEG IS DEFINED BY THE BUDGET ALLOCATED 22
2.5.9 COST-EFFICIENT BUT INFORMATION-RICH LEAD GENERATION STRATEGIES 23
2.5.10 THE REVIVAL OF POTENCY AS THE MOST IMPORTANT LEAD CRITERION 24
2.5.11 WHEN HAS A LG CAMPAIGN DELIVERED SUCCESSFULLY? 27
REFERENCES 31
PART II THE IMPORTANCE OF TARGET IDENTIFICATION FOR GENERATING
SUCCESSFUL LEADS 35
3 "LIGANDABILITY" OF DRUG TARGETS: ASSESSMENT OF CHEMICAL
TRACTABILITY VIA EXPERIMENTAL AND IN SILICO APPROACHES 57
UDO BAUER OND ALEXANDER L BREEZE
3.1 INTRODUCTION 37
3.2 THE CONCEPT OF LIGANDABILITY 39
3.2.1 GENERAL CHARACTERISTICS OF LIGANDABLE TARGETS 39
3.3 THE INTERSECTION OF LIGANDABILITY AND HUMAN DISEASE TARGET SPACE 40
3.3.1 EXPERIMENTAL TECHNIQUES FOR ASSESSING TARGET LIGANDABILITY 42
3.3.1.1 HIGH-THROUGHPUT SCREENING AND SUBSET/YYYYVALIDATION SET"
SCREENING 43
3.3.1.2 FRAGMENT SCREENING 44
3.4 PRACTICAL EXAMPLES OF THE USE OF FRAGMENT SCREENING FOR
LIGANDABILITY
ASSESSMENT 50
3.4.1 CHEMICAL TRACTABILITY ASSESSMENT BY IN SILICO APPROACHES 54
3.4.1.1 POCKET-FINDING AGORITHMS 54
3.4.1.2 DISCRIMINATION FUNCTIONS AND VALIDATION SETS 55
3.4.1.3 SIMULATION-BASED METHODS FOR IDENTIFYING INTERACTION POTENTIALS
56
3.5 CONCLUSIONS AND OUTLOOK 56
REFERENCES 58
4 CHEMISTRY-DRIVEN TARGET IDENTIFICATION 63
YY
YYYYYY CORNEUA-TARADDO, RYAN HICKS, OLA E
YYYYYY
GKV
YYYY
ST, ADAM HENDRICKS,
RONALD TOMUNSON, AND YY\A. PAOLA CASTALDI
4.1 INTRODUCTION 63
4.2 CHEMISTRY-DRIVEN TARGET DISCOVERY: ENABLING BIOLOGY 65
4.2.1 BIOLOGICAL SAMPLES 65
4.2.2 CELLS CULTURED IN 2D 66
4.2.3 CELLS CULTURED IN 3D
YY
ORGANOIDS, AND TISSUES 67
4.2.4 NONHUMAN CELLS AND IOLEO
RGANISM SCREENING 68
4.2.5 FUNCTIONAL ASSAYS AND READOUTS 68
4.3 CHEMISTRY FOR TARGET DISCOVERY 71
4.3.1 SCREENING DECK SELECTION 71
4.3.2 TRIAGING AND PRIORITIZATION OF CHEMICAL MATTER 72
4.3.3 SAR EXPANSION AND PROBE SYNTHESIS FOR TARGET DECONVOLUTION 73
4.4 SMALL-MOLECULE TARGET IDENTIFICATION TECHNIQUES 75
4.4.1 IN SILICO TARGET DECONVOLUTION 75
4.4.2 BIOCHEMICAL PROFILING 77
4.4.3 TARGET DECONVOLUTION CORRELATIONAL TOOLS 78
4.4.4 SUBCELLULAR LOCALIZATION 79
4.4.5 CHEMICAL GENETICS 79
4.4.6 AFFINITY CHEMICAL PROTEOMICS 81
4.4.7 TARGET CORROBORATION 84
4.5 CONCLUSIONS 86
REFERENCES 89
PARTILI HIT GENERATION METHODS 93
5 LEAD GENERATION BASED ON COMPOUND COLLECTION SCREENING 95
DIRK WEIGELT AND ISMET DORANGE
5.1 INTRODUCTION 95
5.2 SCREENING OF EXISTING COLLECTIONS: THE GENERAL WORKFLOW 96
5.2.1 HIGH-THROUGHPUT SCREENING 96
5.2.2 MEDIUM-THROUGHPUT SCREENING: SELECTION METHODS 98
5.3 GENERATION OF NEW SCREENING COMPOUNDS 99
5.3.1 COLLECTION ENHANCEMENT PROGRAMS 102
5.3.2 LIBRAS DESIGN AND COMPOUND SELECTION 102
5.3.2.1 NUMBER OF DIMENSIONS 103
5.3.2.2 ENUMERATION AND FILTERING 104
5.3.2.3 LAYOUT 106
5.3.3 FOCUS ON SYNTHETIC FEASIBILITY 107
5.3.3.1 MULTICOMPONENT REACTIONS 107
5.3.3.2 CLICK CHEMISTRY 108
5.3.3.3 DIVERSITY-ORIENTED SYNTHESIS 108
5.3.4 STRUCTURE-DRIVEN APPROACHES 109
5.3.4.1 PRIVILEGED STRUCTURES 110
5.3.4.2 STRUCTURE-DRIVEN APPROACHES TOWARD UNCHARTERED TERRITORY 112
5.3.5 TARGET FOCUS 114
5.3.5.1 KINASES 114
5.3.5.2 G-PROTEIN-COUPLED RECEPTORS 115
5.3.5.3 ION CHANNELS 116
5.3.5.4 PROTEIN-PROTEIN INTERACTIONS 117
5.4 OTHER CONCEPTS 117
5.4.1 NATURAL PRODUCTS 118
5.4.2 DNA-ENCODED LIBRARIES 119
5.4.3 SPATIALLY ADDRESSED LIBRARIES 120
5.4.4 ON-BEAD SCREENING 120
5.4.5 DYNAMIC COMBINATORIAL CHEMISTRY 121
COCKTAILS AND MIXTURES
121
SUMMARY AND OUTLOOK
122
REFERENCES
123
FRAGMENT-BASED LEAD GENERATION
133
IVON V. EFREMOV AND DANIEL A. ERLONSON
INTRODUCTION
133
SCREENING METHODS
135
HIT VALIDATION
YY
7
LIGAND EFFICIENCY AND OTHER METRICS
138
HIT OPTIMIZATION
139
FRAGMENT GROWING
140
FRAGMENT LINKING
144
PROTEIN-PROTEIN INTERACTIONS
147
GPCRS
151
COMPUTATIONAL APPROACHES
152
CONCLUSIONS
153
REFERENCES 154
RATIONAL HIT GENERATION
159
BERND WELLENZOHN AND ALEXANDER WEBER
INTRODUCTION
159
LEAD GENERATION: TRANSITION STATE AND SUBSTRATE ANALOGS
161
HIT GENERATION BY RATIONAL LIBRARY DESIGN
165
HIT GENERATION BY VIRTUAL SCREENING
167
STRUCTURE-BASED IN ENUMERATED MOLECULES
170
LIGAND-BASED
VS
IN NONENUMERATED VIRTUAL CHEMICAL SPACES
171
HIT GENERATION BY SCAFFOLD REPLACEMENT TECHNOLOGIES
173
HIT GENERATION BY CHEMOGENOMICS APPROACHES
174
SUMMARY
178
REFERENCES
178
COMPETITIVE INTEHIGENCE-BASED LEAD GENERATION AND FAST FOLLOWER
APPROACHES 183
'
YY
JIANG, ZIPIRIG LIU, JOERG HOLERIZ/ AND HUO YANG
INTRODUCTION
183
COMPETITIVE INTELLIGENCE-BASED APPROACH
185
EXAMPLE A: A CASE STUDY FOR THE HYBRID STRATEGY
190
EXAMPLE
C
YY
A CASE STUDY FOR THE FUSED STRATEGY
192
EXAMPLE
C
YY
A CASE STUDY FOR THE FUSED STRATEGY
193
EXAMPLE D: A CASE STUDY FOR THE FUSED STRATEGY
196
EXAMPLE E: A LASE STUDY FOR THE LHIMERA STRATEGY
197
FAST FOLLOWER APPROACH
201
SALFANILAMIDE-BASED FAST FOLLOWER APPROACHES
202
OMEPRAZOLE-BASED FAST FOLLOWER APPROACHES
203
RIMONABANT-BASED FAST FOLLOWER APPROACH
210
REFERENCES
214
YY
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CONTENTS
|XI
9 SELECTIVE OPTIMIZATION OF SIDE ACTIVITIES: AN ALTERNATIVE AND
PROMISING
STRATEGY FOR LEAD GENERATION 221
NORBERT HANDLER, ANDREA WOLKERSTORFER, AND HELMUT BUSCHMANN
9.1 INTRODUCTION 221
9.1.1 DRUG SELECTIVITY AND UNWANTED OR DESIRED SIDE EFFECTS 222
9.2 DEFINITION, RATIONAL
YY
AND CONCEPT OF THE SOSA APPROACH 223
9.2.1 MULTIPLE LIGANDS AND POLYPHARMACOLOGY 224
9.2.2 SAFETY AND BIOAVAILABILITY 225
9.3 DRUGS IN OTHER DRUGS: DRUG AS FRAGMENTS 225
9.4 DRUG REPOSITIONING AND DRUG REPURPOSING 226
9.4.1 OLD DRUGS
YY
6
9.5 THE SOSA APPROACH AND ANALOG DESIGN 227
9.6 PATENTABILITY AND INTERFERENCE RISK OF THE SOSA APPROACH 230
9.6.1 ANALOGIZATION, OPTIMIZATION
YY
AND ISOSTERISM 230
9.7 CASE STUDIES AND EXAMPLES 231
9.7.1 SULFONAMIDES 231
9.7.2 MORPHINE ANALOGS 232
9.7.3 WARFARIN 232
9.7.4 SILDENAFIL (VIAGRA) 232
9.7.5 THALIDOMIDE ANALOGS 233
9.7.6 BUPROPION 234
9.7.7 CHLORPROMAZINE 235
9.7.8 CHLOROTHIAZIDE 235
9.7.9 PROPRANOLOL 235
9.7.10 MINAPRINE ANALOGS 236
9.7.11 VILOXAZINE ANALOGS 237
9.7.12 METHYLATION IN THE SOSA STRATEGY OF DRUG DESIGN 237
9.7.13 DISCOVERY OF NEW ANTIPLASMODIAL COMPOUNDS 239
9.7.14 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM TARGETS AS LEADS FOR
NON-CNS TAGETS 241
9.7.15 MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF
UROKINASE-TYPE PLASMINOGEN ACTIVATOR 242
9.7.16 AMILORIDE ANALOGS AS INHIBITORS OF THE UROKINASE-TYPE PLASMINOGEN
ACTIVATOR 245
9.7.17 FLAVONOIDS WITH AN OLIGOPOLYSULFATED MOIETY: A NEW CLASS OF
ANTICOAGULANT AGENTS 246
9.7.18 CLIOQUINOL 249
9.8 CONCLUSIONS 251
REFERENCES 252
10 LEAD GENERATION FOR CHALLENGING TARGETS 259
YY
YYYYYY
YYYYYY
YY
YYYY
WAN, DENGFENG DO
YY
, HONGMEI SONG, YYYY
YY
YYYY-YY
YY
\ WU,
XUEMIN CHENG, AND JIN LI
10.1 INTRODUCTION 259
10.2 DNA-ENCODEA LIBRA" TECHNOLOGY IN LEAD GENERATION 260
10.2.1 BACKGROUND 260
10.2.2 DNA-RECORDED SYNTHESIS-ASSISTED LIBRARIES 262
10.2.3 DNA-TEMPLATED SYNTHESIS-ASSISTED LIBRARIES 264
10.2.4 ENCODED SELF-ASSEMBLING CHEMICAL LIBRARIES 266
10.2.5 SUMMA
YY
AND PERSPECTIVE 267
10.3 STAPLED PEPTIDE 276
10.3.1 BACKGROUND 276
10.3.2 STRUCTURE, DESIGN, AND SYNTHESIS OF STAPLED PEPTIDE 278
10.3.2.1 STAPLED PEPTIDE STRUCTURE 278
10.3.2.2 STAPLED PEPTIDE DESIGN 280
10.3.2.3 STAPLED PEPTIDE SYNTHESIS 282
10.3.3 STAPLED PEPTIDE SOLUTION A-HELIX CONVERSION MEASUREMENT 283
10.3.4 STAPLED PEPTIDE AFFINITY EVALUATION AND A-HELIX CONTENT
CORRELATION 284
10.3.4.1 SURFACE PLASMON RESONANCE BINDING ASSAYS 284
10.3.4.2 FLUORESCENCE POLARIZATION ASSAY 284
10.3.4.3 STAPLED PEPTIDE AFFINITY AND A-HELIX CONTENT CORRELATION 285
10.3.5 STAPLED PEPTIDE PERMEABILITY 286
10.3.6 PEPTIDE STABILITY ASSAY 288
10.3.7 OUTLOOK 288
10.4 PHENOTYPIC SCREENING 289
10.4.1 INTRODUCTION 289
10.4.2 BASICS FOR ESTABLISHING A PHENOTYPIC SCREEN 291
10.4.2.1 IDENTIFY A "DRUGGABLE" PHENOTYPE AND THE TYPE OF READOUT 291
10.4.2.2 ASAY DESIGN 291
10.4.2.3 HIT SELECTION AND SECONDARY ASSAY 291
10.4.3 TYPICAL PHENOTYPIC ASSAYS 292
10.4.3.1 CELL-VIABILITY ASSAY 292
10.4.3.2 FLUORESCENT IMAGING PLATE READER TECHNOLOGY 293
10.4.3.3 HIGH-CONTENT SCREENING 293
10.4.4 IN VITRO PHENOTYPIC SCREENING 293
10.4.4.1 CLASSIC PHENOTYPIC SCREENING 293
10.4.4.2 PATIENT-DERIVED STEM CELL IN DRUG DISCOVERY 294
10.4.4.3 PHENOTYPIC SCREENING ON IPSC-DERIVED DISEASE MODELS 295
10.4.4.4 HIGH-CONTENT CYTOTOXICITY SCREENING BY IPSC-DERIVED HEPATOC^ES
296
10.5 SUMMA
YY
297
REFERENCES 298
YY YY COABORATYYVE APPROACHES TO LEAD GENERATION 307
FABRIZIO GIORDANETTO, ANNO KARAWAJCZYK, AND GRAHAM SHOWELL
11.1 INTRODUCTION YY
11.2 CREATIVITY 308
11.3 SPEED 308
11.4 RISK SHARING 308
11.5 INTELLECTUAL PROPERTY 309
11.6 COSTS 309
11.7 MANAGEMENT 310
11.8 LILLY'S OPEN INNOVATION DRUG DISCOVERY 310
11.9 MOLECULAR LIBRARY PROGRAM 312
11.10 EU OPENSCREEN 314
11.11 EUROPEAN LEAD FACTORY 315
11.12 MEDICINES FOR MALARIA VENTURE 317
11.13 OPEN SOURCE MALARIA PROJECT 320
11.14 DRUGS FOR NEGLECTED DISEASES INITIATIVE 320
11.15 OPEN LAB FOUNDATION 321
11.16 SCIENTISTS AGAINST MALARIA 322
11.17 OPEN SOURCE DRUG DISCOVERY 323
11.18 YYYY ALLIANCE 323
11.19 SUMMA
YY
324
REFERENCES 325
VOLUME 68B
DEDICATION V
UST OF CONTRIBUTORS XXI
PART IV CONVERTING HITS TO SUCCESSFUL LEADS 329
12 A MEDICINAL CHEMISTRY PERSPECTIVE ON THE HITTO-LEAD PHASE YYN
THE CURRENT ERA OF DRUG DISCOVERY 331
DEAN G. BROWN
12.1 INTRODUCTION 331
199
ACTIVE TO HIT PROCESES 333
12.3 TARGET POTENCY: ENERGETICS OF BINDING 336
12.4 ADDRESING VAST CHEMICAL SPACE: HTL STRATEGIES 345
12.5 MATCHED PAIR ANALYSIS 348
12.6 THE ROLE OF HYDROPHOBICITY AND HTL 351
12.7 PROBING H_BOND DONORS AND ACCEPTORS 353
12.8 STRUCTURE BASED DD IN HTL 356
12.9 STATISTICAL MOLECULAR DESIGN 358
12.10 HIT TO LEAD IS NOT LEAD OPTIMIZATION 359
12.11 SUMMARY YY
REFERENCES 363
13 MOLECULAR RECOGNITION AND ITS IMPORTANCE FOR FRAGMENT-BASED
LEAD GENERATION AND HYYT-T
0
_LEAD 367
THORSTEN NOWAK
13.1 INTRODUCTION 367
13.2 BRIEF SUMMARY OF THE MAIN FACTORS THAT GOVERN MOLECULAR
INTERACTIONS 368
13.3
13.4
13.5
13.6
13.7
13.8
13.9
13.10
13.11
14
14.1
14.2
14.3
14.4
14.5
14.6
14.7
14.8
YY
5
15.1
15.2
15.3
15.3.1
15.3.2
15.3.3
15.3.4
15.3.5
15.4
15.4.1
15.5
15.6
THERMODYNAMICS OF MOLECULAR INTERACTIONS AND IMPACT ON HIT FINDING
AND OPTIMIZATION 369
ENTHALPY AS A KEY DECISION TOOL IN MEDICINAL CHEMIST
YY
371
IMPORTANCE OF ENTHALPIE INTERACTIONS: DRIVERS OF SELECTIVITY
AND SPECIFICITY? 373
FRAGMENT SCREENING HIT OPTIMIZATION: FRAGMENT LINKING 374
INTERSTITIAL WATERS AND THEIR USEFULNESS: CASE STUDIES ON HSP-90 381
FRAGMENTS TO FIND HOT SPOTS IN BINDING POCKETS 385
NONCLASSICAL HYDROGEN BONDS - INTERACTIONS OF HALOGEN ATOMS WITH
N-SYSTEMS AND CARBONYL GROUPS: FACTOR XA AND CATHEPSIN L 386
BINDING MODE DEPENDENCY OF THE EXPERIMENTAL CONDITIONS AND CHEMI
CAL FRAMEWORK OF LIGAND 390
COOPERATIVITY IN BINDING DAO OR DAAO D-AMINO
ACID OXIDASE 391
REFERENCES 394
AFFINITY_BASED SCREENING METHODOLOGIES AND THEIR APPLICATION IN
THE HIT-TO-LEAD PHASE 401
STEFAN GESCHWINDNER
INTRODUCTION 401
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY 402
OPTICAL BIOSENSORS: SURFACE PLASMON RESONANCE AND OPTICAL
WAVEGUIDE GRATING 404
ISOTHERMAL TITRATION CALORIMETRY 407
THERMAL SHIFT ASSAY 411
MASS SPECTROMETRY APPROACHES 412
ENCODED LIBRARY TECHNOLOGIES 414
EMERGING TECHNOLOGIES MICROSCALE THERMOPHORESIS AND
BACKSCATTERING INTERFEROMETRY 417
REFERENCES 418
PREDICTIVE METHODS IN LEAD GENERATION 425
MATTHEW D. SEGOLI AND PETER HUNT
INTRODUCTION 425
COMPOUND PROPERTY PREDICTION 427
MULTIPARAMETER OPTIMIZATION: IDENTIFYING HIGH-QUALITY COMPOUNDS 430
DRUG-LIKE PROPERTIES 430
FILTERS 431
DESIRABILITY FUNCTIONS AND PROBABILISTIC SCORING 432
PARETO OPTIMIZATION 435
EXAMPLE 436
DE NOVO DESIGN: GUIDING THE EXPLORATION OF NOVEL CHEMISTRY 439
EXAMPLE APPLICATION 442
SELECTION: BALANCING QUALITY WITH DIVERSITY 443
CONCLUSIONS 445
REFERENCES 447
LEAD QUALITY 451
JLIUEM NA. NISSLNK, SEBASTIEN DEGORCE, AND KEN PAGE
16.1 INTRODUCTION 451
16.2 PROPERTIES IN DRUG DESIGN 452
16.2.1 PRIMARY ACTIVITY ASSAYS 453
16.2.2 PHYSICOCHEMICAL PROPERTIES 453
16.2.3 DMPK 454
16.2.4 SAFETY 454
16.2.5 OVERALL PROFILES 456
16.3 OPTIMIZING PROPERTIES: USEFUL RULES GUIDES AND SIMPLE METRICS FOR
EARLY-STAGE PROJECTS 457
16.3.1 RULES FOR POTENCY: LIGAND EFFICIENCY MEASURES 457
16.3.2 RULES FOR SAFETY 462
16.3.3 RULES FOR DMPI
YY
AND MODE OF ADMINISTRATION: EARLY-STAGE STRUCTURE-
BASED PROFILING 464
16.3.3.1 SIMPLE DESIGN RULES FOR GOOD DMPK 464
16.3.3.2 OTHER DMPI
YY
DESIGN RULES 465
16.3.4 MULTIOBJECTIVE OPTIMIZATION 466
16.4 PREDICTED DOSE TO MAN AS A MEASURE OF EARLY- AND LATE-STAGE LEAD
QUALITY 467
1^4.1 INTRODUCTION 467
16.4.2 DESCRIPTION OF MODELS AND DATA 469
16.4.3 DATA SUPPORTING TECHNIQUE 471
16.4.3.1 MATCHING ED2M DOSES WITH NORMALIZED OBSERVED
CLINICAL DOSES 472
16.4.3.2 MATCHING YYYYYYYY VALUES FROM ED2M AND CLINICAL STUDIES 472
16.4.4 FLAGGING POTENTIAL CANDIDATE DRUGS USING ED2M 473
16.4.5 DETERMINING PROPERTIES THAT DRIVE ED2M PREDICTIONS
IO
TYYLYYIET\ES 474
16.5 SUMMARY 480
REFERENCES 481
PARTV HYPOTHESIS-DRIVEN LEAD OPTIMIZATION 487
YY7 THE STRATEGIES AND POLITICS OF SUCCESSFUL DESIGN, MAKE, TEST, AND
ANALYZE
(DMTA) CYCLES IN LEAD GENERATION 489
STEVEN 5. WESOYYOWSKI AND DEAN G. BROWN
17.1 DMTA CYCLES: PERSPECTIVES FROM HISTORY 490
17.2 TEST: WHAT ASSAYS
YY
IN WHAT ORDER
YY
AND WHY? 494
17.3 ADDITIONAL ADVICE FOR "TEST" COMPONENT OF DMTA 496
17.4 DESIGN: L
A
T TO MAKE AND WHY? 496
17.5 ADDITIONAL ADVICE FOR "DESIGN" COMPONENT OF DMTA 500
17.6 MAKE: CHALLENGES AND STRATEGIES FOR SYNTHESIS 501
17.7 ADDITIONAL ADVICE FOR THE "MAKE" COMPONENT OF DMTA 502
17.8 ANALYZE: MAKING SENSE OF TH
A
T'S BEEN DONE AND FORMULATING SENSIBLE
PLANS FOR THE NEXT DESIGNS 502
17.9 ADDITIONAL ADVICE FOR "ANALYZE" COMPONENT OF DMTA 508
17.10 RESULTS: DO LEAD OPTIMIZATION TEAMS GET WHAT
THEY NEED? 508
REFERENCES 509
PART VI RECENT LEAD GENERATION SUCCESS STORIES 513
18
18.1
18.2
18.3
18.3.1
18.3.2
18.3.3
18.3.4
18.4
18.5
LEAD GENERATION PAVED THE WAY FOR THE DISCOVERY OF A NOVEL YYYY INVERSE
AGONIST CLINICAL CANDIDATE 515
CHRISTOPHE GENICOT AND LAURENT PROVINS
INTRODUCTION SIS
HIT IDENTIFICATION 517
LEAD GENERATION 521
EXPLORATION OF OXAZOLINE SUBSTITUTION 523
RIGIDIFICATION OF PROPOXY LINKER 531
OXAZOLINE/OXAZOLE SURROGATES: LACTAMS 533
CONCLUSIONS 536
LEAD OPTIMIZATION AND CANDIDATE SELECTION 537
CONCLUSIONS 543
ACKNOWLEDGMENTS 544
REFERENCES 544
19 VORAPAXAR: FROM LEAD IDENTIFICATION TO FDA APPROVAL 547
SAMUEL CHOCKALAMANNIL AND MARIAPPAN CHELLIAH
19.1 INTRODUCTION 547
19.2 BACKGROUND INFORMATION ON ANTIPLATELET AGENTS 549
19.3 THROMBIN RECEPTOR (PROTEASE-ACTIVATED RECEPTOR-L) ANTAGONISTS AS A
NOVEL CLASS OF ANTIPLATELET AGENTS 550
19.4 MECHANISM OF THROMBIN RECEPTOR ACTIVATION 550
19.5 PRECLINICAL DATA SUPPORTING THE ANTIPLATELET EFFECT OF THROMBIN
RECEPTOR ANTAGONISTS 551
19.6 HIMBACINE-DERIVED THROMBIN RECEPTOR ANTAGONISTS 552
19.6.1 LEAD IDENTIFICATION 552
19.6.2 LEAD GENERATION OF HIMBACINE-DERIVED THROMBIN RECEPTOR
ANTAGONIST HIT 553
19.6.2.1 STRUCTURE-ACTIVITY RELATIONSHIP STUDIES 555
19.6.2.2 FIRST-GENERATION THROMBIN RECEPTOR ANTAGONISTS 556
19.6.2.3 IN VIVO METABOLISM OF HIMBACINE DERIVATIVES 558
19.6.2.4 GENERATION OF ARYL HIMBACINE LEADS 561
19.6.2.5 SECOND-GENERATION LEADS THAT INCORPORATE HETEROATOMS IN THE
C-RING 562
19.6.2.6 IDENTIFICATION OF NOR-SECO HIMBACINE LEAD 564
19.6.3 DISCOVERY OF VORAPAXAR (SCH 530348) 565
19.6.3.1 CLINICAL STUDIES OF VORAPAXAR 567
19.7 CONCLUSIONS 569
ABBREVIATIONS 570
ACKNOWLEDGMENTS 570
REFERENCES 571
20 LEAD GENERATION APPROACHES DELIVERING INHALED PA-ADRENORECEPTOR
AGONIST DRUG CANDIDATES 575
MICHAEL STOCKS AND LILIAN ALCARAZ
20.1 INTRODUCTION 575
90 9 LEAD GENERATION EXERCISES TO DISCOVER BOAR AGONIST CLINICAL
CANDIDATES 577
20.3 ASTRAZENECA LEAD GENERATION EXERCISES TO DISCOVER SS2AR AGONIST
CLINICAL CANDIDATES 587
20.4 SUMMARY 593
REFERENCES 593
21 GPR81 HTS CASE STUDY 597
ERIC WELLNER AND OLA FJELLSTROM
21.1 GENERAL REMARKS 597
21.2 THE TARGET 598
21.3 SCREENING CASCADE 599
21.4 COMPOUND SELECTION (10 1
YY
VALIDATION SET) 602
21.5 HTS 606
21.5.1 CSE 608
21.5.2 SINGLECONCENTRATION COUNTERSCREEN 614
21.5.3 CLUSTERING 615
21.5.4 CLUSTER EXPANSION AND NEAREST NEIGHBOURS 618
21.6 HIT EVALUATION 618
21.6.1 POTENCY, EFFICACY, AND CURVES 618
21.6.2 BINDING KINETICS 621
21.6.3 CONCENTRATION-RESPONSE COUNTERSCREEN 622
21.6.4 HIT ASSESSMENT 622
21.6.4.1 SIZE AND LIPOPHILICITY EFFICIENCY ASSESSMENT 622
21.6.4.2 SECONDARY PHARMACOLOGY ASSESSMENT 626
21.6.5 SECONDARY SCREENING CASCADE AND HIT EXPANSION 630
21.6.6 BIOLOGICAL EFFECT ASSAY 634
21.7 ALTERNATIVE LEAD GENERATION STRATEGIES 638
21.7.1 PEPDUCINS AND OTHER MODIFIED PEPTIDES 641
91
YY CONCLUSIONS 645
REFERENCES 646
22 DEVELOPMENT OF INFLUENZA VIRUS SIALIDASE INHIBITORS 651
MAURO PASCOLUTTI/ ROBIN J. THOMSON, OND MARK VON ITZSTEIN
22.1 INTRODUCTION 651
22.2 TARGETS FOR ANTIINFLUENZA DRUG DEVELOPMENT: RECEPTOR BINDING AND
RECEPTOR CLEAVAGE 652
22.2.1 TARGETING RECEPTOR BINDING BY HAEMAGGLUTININ 654
22.2.2 TARGETING RECEPTOR DESTRUCTION BY SIALIDASE 655
22.2.3 INFLUENZA VIRUS SIALIDASE: STRUCTURE AND MECHANISM 656
22.3 DEVELOPMENT OF INFLUENZA VIRUS SIALIDASE INHIBITORS 658
22.3.1 THE DEVELOPMENT OF ZANAMIVIR: PROOF OF CONCEPT AND FIRST-IN-CLASS
SIALIDASE INHIBITOR DRUG 659
22.3.1.1 TEMPLATE SELECTION 659
22.3.1.2 STRUCTURE-BASED INHIBITOR DESIGN 662
22.3.1.3 X-RAY CRYSTALLOGRAPHIC CONFIRMATION OF INHIBITOR BINDING MODE
665
22.3.1.4 SELECTIVITY FOR INFLUENZA VIRUS SIALIDASE OVER HUMAN SIALIDASES
666
22.3.1.5 EFFICACY AGAINST VIRUS REPLICATION 667
22.3.1.6 MODE OF ADMINISTRATION OF THE HIGHLY POLAR DRUG 667
22.3.1.7 MODIFYING THE PRESENTATION OF ZANAMIVIR. PRODRUGS AND
MULTIVALENCY 668
22.3.2 SIALIDASE INHIBITOR DEVELOPMENT ON NONCARBOHYDRATE SCAFFOLDS 671
22.3.2.1 A SIALIDASE INHIBITOR BASED ON A CYCLOHEXENE SCAFFOLD: THE
DEVELOP-
MENT OF OSELTAMIVIR 671
22.3.2.2 A SIALIDASE INHIBITOR BASED ON A CYCLOPENTANE SCAFFOLD:
THE DEVELOPMENT OF PERAMIVIR 673
22.3.3 MONITORING RESISTANCE TO INFLUENZA VIRUS SIALIDASE INHIBITORS 675
22.4 SUMMARY AND FUTURE DIRECTIONS 676
REFERENCES 676
23 THE DISCOVERY OF CATHEPSIN A INHIBITORS: A PROJECT-ADAPTED FRAGMENT
APPROACH BASED ON HTS RESULTS 687
SVEN RUF, CHRISTIAN BURLING, HERMAN SCHREUDER, WOLFGANG LINZ, DOMINIK
LINZ,
HARTMUT RDTTERI/ GEORG HORSTICK/ MARKUS KOHLMANN, KOTJA KROLL, KLAUS
WIRTH,
AND THORSTEN SADOWSKI
23.1 GENERAL BACKGROUND 687
23.2 CATHEPSIN A ENZYME 687
23.2.1 STRUCTURAL BIOLOGY AND CATANIE MECHANISM 687
23.2.2 STRUCTURAL AND CATAL^IC FUNCTIONS OF CATA 689
23.2.3 TISSUE DISTRIBUTION AND SUBSTRATES 689
23.2.4 NATURAL PRODUCTS AND SYNTHETIC PEPTIDES AS INHIBITORS OF CATA 690
23.3 CATA AND THE LINK TO CARDIOVASCULAR DISEASE 691
23.4 LEAD DISCOVERY 692
23.4.1 HIGH-THROUGHPUT SCREENING AND DATA ANALYSIS 692
23.4.2 EVALUATION OF H
T SERIES 693
23.4.2.1 COVALENT INHIBITOR SERIES 693
23.4.2.2 MALONAMIDE SERIES 697
23.4.2.3 PYRAZOLONE HIT SERIES 698
23.4.3 EXPLORATIVE CHEMISTRY DELIVERS A NOVEL LEAD STRUCTURE YY
23.4.3.1 CRYSTAL STRUCTURE OF 9B BOUND TO CATA 705
23.5 LEAD OPTIMIZATION 705
23.6 TOWARD AN IN VIVO PROOF OF CONCEPT 711
23.7 SUMMARY AND CONCLUSIONS 713
REFERENCES 714
24 LEAD STRUCTURE DISCOVERY FOR NEGLECTED DISEASES: PRODUCT DEVELOPMENT
PARTNERSHIPS DRIVING DRUG DISCOVERY 717
JEREMY N. BURROWS AND TAKUSHI KANEKO
24.1 INTRODUCTION 717
24.2 MALARIA AND MEDICINES FOR MALARIA VENTURE 719
24.3 MALARIA LEAD GENERATION STRATEGY 719
24.4 HIT IDENTIFICATION STRATEGIES 722
24.5 OPTIMIZATION OF A MARKETED ANTIMALARIAL CHEMOTYPE 723
24.6 TARGET-BASED APPROACHES 723
24.7 ASEXUAL BLOOD-STAGE PHENOTYPIC SCREENING 724
24.8 WHOLE-CELL SCREENING: RESULTS 725
24.9 REPOSITIONING OF CLINICAL CANDIDATES DEVELOPED FOR OTHER
INDICATIONS 726
24.10 CASE STUDIES 727
24.10.1 DIHYDROOROTATE DEHYDROGENASE (DHODH) 727
24.10.2 WBNIP-SPLL SCREENING 728
24.11 SCREENING FOR MALARIA ERADICATION 729
24.12 TUBERCULOSIS AND THE GLOBAL ALLIANCE FOR TUBERCULOSIS DRUG
DEVELOP-
MENT (YYYY ALLIANCE) 729
24.13 TARGET PRODUCT PROFILES 730
24.14 YYYY ALLIANCE'S MISSION 730
24.15 HIT GENERATION STRATEGIES FOR YYYY 732
24.16 EXAMPLES OF PHENOTYPIC SCREENS 733
24.17 CONCLUSIONS 741
REFERENCES 741
25 A FRAGMENTATION ENUMERATION APPROACH TO GENERATING
NOVEL DRUG LEADS 747
PRAVIN
S.
IYER AND MANORANJAN PANDA
25.1 INTRODUCTION 747
25.2 PRINCIPLE 748
25.3 RESEARCH METHODOLOGY 748
25.3.1 FRAGMENTATION 749
25.3.1.1 ORIGIN OF PARENT MOLECULES 749
25.3.1.2 CORES AND DAUGHTERS 749
25.3.1.3 NONFLAT CORES 751
25.3.2 INTELLIGENT RECOMBINATION AND ENUMERATION 754
25.4 EVALUATION 754
25.4.1 PRELIMINARY EXPERIMENTAL EVALUATION 755
25.4.2 IN SILICO EVALUATION 755
25.4.3 VIRTUAL SCREENING USING ENZYME-LIGAND DOCKING 756
25.5 SUMMARY 758
REFERENCES 759
\
YYYY
DEK 761 |
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| author2 | Holenz, Jörg 1968- |
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| author_GND | (DE-588)118150243 |
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| id | DE-604.BV043556331 |
| illustrated | Not Illustrated |
| indexdate | 2024-08-03T02:59:26Z |
| institution | BVB |
| isbn | 3527333290 9783527333295 9783527677047 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-028971485 |
| open_access_boolean | |
| physical | 2 Bände |
| publishDate | 2016 |
| publishDateSearch | 2016 |
| publishDateSort | 2016 |
| publisher | Wiley-VCH Verlag GmbH & Co. KGaA |
| record_format | marc |
| series2 | Methods and principles in medicinal chemistry |
| spelling | Lead generation methods, strategies, and case studies edited by Jörg Holenz Weinheim Wiley-VCH Verlag GmbH & Co. KGaA [2016] © 2016 2 Bände txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry volume 68 Arzneimittelforschung (DE-588)4003120-2 gnd rswk-swf Biowissenschaften Chemical Informatics Chemie Cheminformatik Chemistry Chemoinformatik Drug Discovery & Development Life Sciences Molecular Biology Molekularbiologie Wirkstoffforschung Wirkstoffforschung u. -entwicklung Arzneimittelforschung (DE-588)4003120-2 s DE-604 Holenz, Jörg 1968- (DE-588)118150243 edt Erscheint auch als Online-Ausgabe, EPUB 978-3-527-67706-1 Erscheint auch als Online-Ausgabe, MOBI 978-3-527-67705-4 Erscheint auch als Online-Ausgabe, PDF 978-3-527-67707-8 X:MVB text/html http://deposit.dnb.de/cgi-bin/dokserv?id=5327568&prov=M&dok_var=1&dok_ext=htm Inhaltstext B:DE-101 application/pdf http://d-nb.info/1074254597/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=028971485&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Lead generation methods, strategies, and case studies Arzneimittelforschung (DE-588)4003120-2 gnd |
| subject_GND | (DE-588)4003120-2 |
| title | Lead generation methods, strategies, and case studies |
| title_auth | Lead generation methods, strategies, and case studies |
| title_exact_search | Lead generation methods, strategies, and case studies |
| title_full | Lead generation methods, strategies, and case studies edited by Jörg Holenz |
| title_fullStr | Lead generation methods, strategies, and case studies edited by Jörg Holenz |
| title_full_unstemmed | Lead generation methods, strategies, and case studies edited by Jörg Holenz |
| title_short | Lead generation |
| title_sort | lead generation methods strategies and case studies |
| title_sub | methods, strategies, and case studies |
| topic | Arzneimittelforschung (DE-588)4003120-2 gnd |
| topic_facet | Arzneimittelforschung |
| url | http://deposit.dnb.de/cgi-bin/dokserv?id=5327568&prov=M&dok_var=1&dok_ext=htm http://d-nb.info/1074254597/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=028971485&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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