Hit and lead profiling: identification and optimization of drug-like molecules
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2009
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| Schriftenreihe: | Methods and Principles in Medicinal Chemistry
43 |
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| Beschreibung: | XXX, 503 S. Ill., graph. Darst. 240 mm x 170 mm |
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| 245 | 1 | 0 | |a Hit and lead profiling |b identification and optimization of drug-like molecules |c ed. by Bernard Faller ... |
| 264 | 1 | |a Weinheim, Bergstr |b Wiley-VCH Verlag GmbH & Co. KGaA |c 2009 | |
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| 490 | 1 | |a Methods and Principles in Medicinal Chemistry |v 43 | |
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IMAGE 1
CONTENTS
LIST OF CONTRIBUTORS XIX PREFACE XXV
A PERSONAL FOREWORD XXV77
PART I
1 PROCESS LOGISTICS, TESTING STRATEGIES AND AUTOMATION ASPECTS 3
HANSJOERG HAAS, ROBERT S. DEWITTE, ROBERT DUNN-DUFAUIT, AND ANDREAS
STELZER 1.1 INTRODUCTION 3
1.2 THE PROCESS FROM RAW INGREDIENTS TO DATA 3
1.2.1 COMPOUND MANAGEMENT 5 1.2.2 CELLBIOLOGY 6
1.2.3 LEAD PROFILING 7
1.2.4 LIQUID CHROMATOGRAPHY/MASS SPECTROMERRY 7 1.3 DMPK TESTING
STRATEGIES: THE PROCESS FROM DATA TO DECISIONS S 1.4 NEW QUESTIONS, NEW
ASSAYS AND NEW TECHNOLOGIES CHALLENGE THE PROCESS 10
1.5 ORGANIZATIONAL MODELS TO SCALE UP THE PROCESS 11 1.5.1 FOOD COURT U
1.5.1.1 THE FAST FOOD RESTAURANT 12 1.5.1.2 THE FAMILY RESTAURANT CHAIN
12 1.6 CRITICAL FACTORS TO IMPROVE THE PROCESS 13 1.7 MATERIALS IN
ADME/TOX SCREENING 14
1.8 MACHINES AND EQUIPMENT IN ADME/TOX SCREENING 17 1.8.1 LIQUID
HANDLERS 17
1.8.2 DETECTION AND ANALYSIS 17 1.9 SOFTWARE, DATA RETRIEVAL, ANALYSIS,
MANIPULATION AND INTERPRETATION 78 1.10 ENVIRONMENT AND MANAGEMENT =
ORGANIZATIONAL STRUCTURE IN ADME/TOX SCREENING 19
HIT AND LEAD PROFDING. RDITED BY BERNARD FALLER AND L^ASZLO URBAN
COPYRIGHT 2009 WII.EY-VCH VERLAG GMBH & CO. KCAA, WEINHEIM
IMAGE 2
VI CONTENTS
1.11
1.11 1.11 1.11 1.11
1.12
1 1.1 1.2 1.3
METHODS IN ADME/TOX SCREENING 20 EXAMPLES OF WHOLE-PROCESS APPROACHES 20
AUTOMATION ISLANDS WITH MANUAL DATA UPLOAD TO A UMS SYSTEM 21 COMPLETE
PHYSICAL INTEGRATION AND AUTOMATION 21 FEDERATED PHYSICAL AUTOMATION
WITH SOFTWARE INTEGRATION 22 CONCLUSIONS 22 REFERENCES 23
2 PREDICTION OF DRUG-LIKENESS AND ITS INTEGRATION INTOTHE DRUG DISCOVERY
PROCESS 25 ANSGAR SCHUFFENHAUER AND MEIR CIICK 2.1 INTRODUCTION 25
2.2 COMPUTATIONAL PREDICTION OF DRUG-LIKENESS 26 2.2.1 MACHINE LEARNING
26
2.2.2 EMPIRICAL RULES AND THEIR BASIS 30 2.2.3 DRUG-LIKENESS OF NATURAL
PRODUCTS 32 2.2.4 DO IIGANDS OF DIFFERENT TARGET CLASSES DIFFER IN THEIR
DRUG-LIKE PROPERTIES? 34 2.2.5 UNWANTED STRUCTURAL ELEMENTS 34 2.3 WHAT
IS THE BEST PRACTICE IN UTILIZING DRUG-LIKENESS IN DRUG
DISCOVERY? 35
2.4 CONCLUDING DISCUSSIONS 37
REFERENCES 38
3 INTEGRATIVE RISK ASSESSMENT 41
BERNARD FALLER AND LASZLO URBAN THE TARGET COMPOUND PROFILE 41
INTRODUCTION 41 THE IMPORTANCE OF THE PROJECTED CLINICAL COMPOUND
PROFILE
IN EARLY DRUG DISCOVERY 42 THE IMPACT OF DCLIVCRY ON THE DESIGN OF THE
DRUG DISCOVERY PROCESS 43 THE CONCEPT OF HIERARCHICAL TESTING IN PRIMARY
AND FOLLOW-UP
ASSAYS 45 IMPACT OF TURN-AROUND TIME 47 ASSAY VALIDANON AND REFERENCE
COMPOUNDS 47 REQUIREMENTS OF PROFILING ASSAY QUALITY 48
THE IMPORTANCE OF FOLLOW-UP ASSAYS 48 EXPOSURE ASSAYS 49 BASIC
ABSORPTION ASSAYS 49 SOLUBILITY ASSAYS 50 PERMEABILITY ASSAYS 50 ACTIVE
TRANSPORTS AND EFFLUX 51
METABOLISM 51 DISTRIBUTION AND ELIMINATION 5/ DRUG-DRUG INTERACTIONS 53
3.1 3.1 3.1
3.1
3.2
3.2 3.2 3.2 3.2
3.3 3.3 3.3
1 2
3
1 2
3 4
1 1.1
3.3.1.2 3.3.2
3.3 3.3 3.3
,3 ,4 ,5
IMAGE 3
CONTENTS VII
3.3.6 IVIV CORRELATIONS 53
3.4 ITERATIVE ASSAYS: LINK BETWEEN ASSAYS 54 3.5 SPECIFIC SAFETY
PROFILING ASSAYS 56 3.5.1 SENSITIVITY AND SPECIFICITY OF SAFETY ASSAYS
SHOULD BE ADJUSTED TO THE PHASE OF DRUG DISCOVERY 58
3.5.2 ADDRESSING SPECIES SPECIFICITY IN EARLY IN VITRO ASSAYS 58 3.6
DATA REPORTING AND DATA MINING 59
3.6.1 DECISION MAKING: TREND ANALYSIS, GO/NO GO DECISIONS 60 3.7
INTEGRATIVE RISK ASSESSMENT 61
REFERENCES 64
PART II
4 SOLUBILITY AND AGGREGATION 71
WILLIAM H. STRENG
4.1 IMPORTANCE OF SOLUBILITY 71
4.2 FACTORS INFLUENCING SOLUBILITY 72
4.3 METHODS USED TO DETERMINE SOLUBILITY 74 4.4 APPROACHES TO
SOLUBILITY' 76
4.5 SOLUBILITY IN NON-AQUEOUS SOLVENTS AND CO-SOLVENTS 78 4.6
SOLUBILITY'AS A FUNCTION OF PH 79
4.7 EFFECT OF AGGREGATION UPON SOLUBILITY 83 4.8 DEPENDENCE OF
DISSOLUTION UPON SOLUBILITY' 86 4.9 PARTITIONING AND THE EFFECT OF
AGGREGATION 87 4.10 SOLUBILITY IN SIMULATED BIOLOGICAL FLUIDS 89
REFERENCES 90
IN SILICO TOOLS AND IN VITRO HTS APPROACHES TO DETERMINE LIPOPHILICITY
DURING THE DRUG DISCOVERY PROCESS 91 SOPHIE MARTEL, VINCENT GASPARIK,
AND PIERRE-ALAIN CARRUPT INTRODUCTION 91
VIRTUAL FILTERING: IN SILICO PREDKTION OF LOG P AND LOG D 92
LIPOPHILICITY OF NEUTRAL SUBSTANCES: IN SUEICO METHODS TO PREDICT LOG P^
92 2D FRAGMENTAL APPROACHES 92
PREDICTION METHODS BASED ON 3-D MOLECULAR STRUCTURE 95 GENERAL COMMENTS
ON THE PREDICTION OF LOG P OTT 96 PREDICTION MODELS FOR LOG P IN OTHER
SOLVENT/WATER SYSTEMS OF NEUTRAL COMPOUNDS 97 PREDICTION MODELS FOR LOG
P OF IONIC SPECIES (LOG P 1 ) 97
EXPERIMENTAL FILTERING: THE ADMET CHARACTERIZATION OF A HIT COLLECTION
98 HTS LOG P/LOG D DETERMINATION BASED ON MICROTITERPLATE FORMAT 98
CHROMATOGRAPHIE METHODS 100
5.1 5.2 5.2
5.2 5.2 5.2 5.2
.1
.1.1 .1.2 .1.3 .2
5.2.3 5.3
5.3 5.3 .1 .2
IMAGE 4
VIII CONTENTS
5.3.2.1 REVERSE-PHASE LIQUID CHROMATOGRAPHY 100
5.3.2.2 IMMOBILIZED ARTIFICIAL MEMBRANES 102 5.3.2.3 HYDROPHILIC
INTERACTION CHROMATOGRAPHY 103 5.3.2.4 CAPILLARY ELECTROPHORESIS 104
5.3.3 A GLOBAL VIEW ON IN VITRO HTS METHODS TO MEASURE
LOG P/LOG D 104
5.4 CONDUDING REMARKS: EFFICACY OR ACCURACY DILEMMA 105 REFERENCES 107
6 MEMBRANE PERMEABILITY - MEASUREMENT AND PREDICTION IN DRUG DISCOVERY
117 KIYOHIKO SUGANO, LOURDES CUCURULLSANCHEZ, AND JOANNE BENNETT 6.1
OVERVIEW OF MEMBRANE PERMEATION 117
6.1.1 STRUCTURE, PHYSIOLOGY AND CHEMISTRY OF THE MEMBRANE 117 6.1.2
PASSIVE TRANSCELLULAR PATHWAY: PH PARTITION THEORY AS THE BASIS OF
UNDERSTANDING MEMBRANE PERMEABILITY 118 6.1.3 PARACELLULAR PATHWAY 119
6.1.4 ACTIVE TRANSPORTERS 119 6.1.5 IN VITRO-IN VIVO EXTRAPOLATION 119
6.2 IN VITRO CELL MODELS 121
6.2.1 INTESTINAL CELL CULTURE MODELS 121 6.2.2 BBB CELL CULTURE MODELS
122 6.2.3 CELL MODELS TO STUDY ACTIVE TRANSPORTERS 123 6.2.4 CORRELATION
OF IN VITRO MODELS TO HUMAN P ^ A ND FRACTION
ABSORBED DATA 124
6.2.5 CORRELATION OF CELL CULTURE MODELS WITH IN VIVO BRAIN PENETRATION
124 6.3 ARTIFICIAL MEMBRANES 125
6.3.1 PARTITION AND PERMEATION 125 6.3.2 PARALLEL ARTIFICIAL MEMBRANE
PERMEATION ASSAY: RECENT PROGRESS 126 6.3.2.1 UNDERSTANDING PAMPA 126
6.3.2.2 VARIATION OF PAMPA: RECENT PROGRESS 127
6.3.2.3 PHOSPHOLIPID VESIDE PAMPA 127 6.3.2.4 PHOSPHOLIPID-OCTANOL PAMPA
127 6.3.2.5 TRI-LAYER PAMPA 127 6.3.2.6 MUCUS LAYER ADHERED PAMPA 127
6.3.3 APPLICATION OF PAMPA FOR DRUG DISCOVERY 128 6.4 LIMITATION OF IN
VITRO ASSAYS 128
6.4.1 IMPACT OF UWL ON PERMEABILITY 128 6.4.2 MEMBRANE BINDING 129
6.4.3 LOW SOLUBILITY 129
6.4.4 DIFFERENCE OF THE PARACELLULAR PATHWAY 129 6.4.5 INTERLABORATORY
VARIABILITY 129 6.5 COMPUTATIONAL APPROACHES/IN SILICO MODELING 130
IMAGE 5
CONTENTS IX
6.5.1 IN VIVO SYSTEMS 130
6.5.2 IN VITRO CELLULAR MEMBRANE SYSTEMS 132 6.5.3 ARTIFICIAL MEMBRANES
134 6.5.4 PERSPECTIVES 135
6.6 OUTLOOK 135
REFERENCES 136
7 DRUG METABOLISM AND REACTIVE METABOLITES 145 ALAN P. WATT
7.1 INTRODUCTION TO DRUG METABOLISM 145 7.1.1 HISTORICAL PERSPECTIVE 145
7.1.2 IN VITRO METABOLISM 146 7.1.3 CYTOCHROME P450 148 7.1.4 PREDICTION
OF DRUG METABOLISM 149
7.2 ADVERSE DRUG REACTIONS 249
7.2.1 ADR CLASSIFICATION 150 7.2.2 IDIOSYNCRATIC DRUG REACTIONS 150 7.3
BIOACTIVATION 151
7.3.1 DEFINITION 151
73.2 REACTIONS OF ELECTROPHILIC METABOLITES 151 7.3.3 GLUTATHIONE 151
7.3.4 DETECTION OFGSH CONJUGATES 151 7.3.5 ACYL GLUCURONIDES 152 7.3.6
FREE RADICALS AND OXIDATIVE STRESS 152 7.4 REACTIVE METABOLITES AND
IDIOSYNCRATIC TOXICITY 153
7.4.1 THE HAPTEN HYPOTHESIS 153 7.4.1.1 IMMUNE-MEDIATED CUTANEOUS
REACTIONS 153 7.4.2 THE DANGER HYPOTHESIS 153 7.4.3 ALTERNATE
PERSPECTIVES TO COVALENT BINDING 154
7.4.3.1 NON-TOXICOLOGICAL COVALENT BINDING 154 7.4.3.2 COVALENT BINDING
AS DETOXIFICATION 154 7.5 MEASUREMENT OF REACTIVE METABOLITES 155 7.5.1
TRAPPING ASSAYS 155
7.5.1.1 SOFT NUCLEOPHILES 155 7.5.1.2 HARD NUCLEOPHILES 155 7.5.2 MASS
SPECTROMETRIC DETECTION OF GSH CONJUGATES AND MERCAPTURIC ACIDS 155
7.5.3 RADIOMETRIE ASSAYS 256 7.5.3.1 COVALENT BINDING TO LIVER
MICROSOMES 157 7.5.3.2 EX VIVO COVALENT BINDING 157 7.5.3.3 14 CCYANIDE
TRAPPING 157
7.5.3.4 RADIOLABELED SOFT NUCLEOPHILE TRAPPING 758 7.5.4 ALTERNATE
APPROACHES 158 7.6 STRATEGIES FOR MINIMIZING REACTIVE METABOLITE RISK
159 7.6.1 DOSE AND EXPOSURE 159
IMAGE 6
CONTENTS
7.6.2 STRUCTURAL ALERTS 159
7.6.3 CASCADE FOR RADIOLABELED COVALENT BINDING EXPERIMENTS 160 7.6.4
CRITERIA FOR PROGRESSION 160 7.7 CONCLUSIONS 160
REFERENCES 161
8 DRUG-DRUG INTERACTIONS: SCREENING FOR LIABILITY AND ASSESSMENT OFRISK
165 RUTH HYLAND, R. SCOTT OBACH, CHAD STONER, MICHAEL WEST, MICHAEL R.
WESTER, KURESH YOUDIM, AND MICHAEL ZIENTEK
8.1 INTRODUCTION 165
8.2 IN SILICO APPROACHES 767
8.3 PERPETRATORS OF DRUG-DRUG INTERACTIONS: ENZYME INHIBITION 169 8.3.1
COMPETITIVE INHIBITION 169 8.3.2 CONVENTIONAL CYP INHIBITION SCREEN 170
8.3.3 FLUORESCENT INHIBITION SCREEN 172 8.3.4 DDI SINGLE POINT VERSUS IC
S0 DETERMINATIONS 172 8.3.5 DDI COCKTAIL ASSAY 173
8.3.6 MECHANISM-BASED INHIBITION 174 8.4 PERPETRATORS OF DRUG-DRUG
INTERACTIONS: ENZYME INDUCTION 176 8.4.1 LIGAND BINDING ASSAY 177 8.4.2
REPORTER GENE (TRANSACTIVATION) ASSAYS 178 8.4.3 OVERALL EVALUATION OF
HIGH-THROUGHPUT INDUCTION ASSAYS 179 8.5 DRUG-DRUG INTERACTIONS; VICTIMS
OF INTERACTION; REACTION
PHENOTYPING 1 79
8.5.1 CHEMICAL INHIBITION 180
8.5.2 RECOMBINANT HUMAN CYP ENZYMES 181 8.6 PREDICRIONS OF DRUG-DRUG
INTERACTIONS 182 8.6.1 NEW COMPOUNDS AS POTENTIAL DDI PERPETRATORS 183
8.6.2 NEW COMPOUNDS AS POTENTIAL DDI VICTIMS 184
8.7 SUMMARY 187
REFERENCES 188
9 PLASMA PROTEIN BINDING AND VOLUME OF DISTRIBUTION: DETERMINATION,
PREDICTION AND USE IN EARLY DRUG DISCOVERY 197
FRANCO LOMBARDO, R. SCOTT OBACH, AND NIGELJ. WATERS 9.1 INTRODUCTION:
IMPORTANCE OF PLASMA PROTEIN BINDING 197
9.2 IMPACT OF PLASMA PROTEIN BINDING ON PK, EXPOSURE, SAFETY MARGINS,
POTENCY SCREENS AND DRUG-DRUG INTERACTION 197 9.3 METHODOLOGIES FOR
MEASURING PLASMA PROTEIN BINDING 201 9.4 PHYSICOCHEMICAL DETERMINANTS
AND IN SILICO PREDICTION OF PLASMA
PROTEIN BINDING 206
9.5 VOLUME OF DISTRIBUTION: GENERAL CONSIDERATIONS AND APPLICATIONS TO
EXPERIMENTAL PHARMACOKINETICS AND DRUG DESIGN 208 9.5.1 PREDICTION OF
HUMAN VOLUME OF DISTRIBUTION 210
IMAGE 7
CONTENTS XI
9.5.1.1 PREDICTION OF HUMAN VOLUME OF DISTRIBUTION FROM ANIMAL
PHARMACOKINETIC DATA 210 9.5.1.2 PREDICTION OF HUMAN VOLUME OF
DISTRIBUTION FROM IN VITRO DATA 212 9.5.1.3 PREDICTION OF HUMAN VOLUME
OF DISTRIBUTION FROM IN SUEICO
METHODS 213
9.6 RELATIONSHIP BETWEEN CLEARANCE, VDSS AND PLASMA PROTEIN BINDING 213
9.7 SUMMARY AND CONCLUSIONS 214
REFERENCES 215
10 PUTTING IT ALL TOGETHER 221
PAMELA BERN?, NEIL PARROTT, MICAEIA REDDY, PASCALE DAVID-PIERSON, AND
THIERRY LAVE
10.1 CHALLENGES IN DRUG DISCOVERY 221 10.2 MCTHODOLOGICAL ASPECTS 222
10.2.1 PBPK 222
10.2.2 PK/PD 225
10.3 STRATEGIE USC OF PBPK DURING DRUG DISCOVERY 226 10.4 STRATEGIE USE
OF PK/PD DURING DRUG DISCOVERY 227 10.5 APPLICATION DURING LEAD
IDENTIFICATION 227 10.6 APPLICATION DURING LEAD OPTIMIZATION 232 10.7
APPLICATION DURING CLINICAL LEAD SELECTION 235
10.8 LIMITATIONS WITH CURRENT METHODOLOGY AND APPROACHES 236 10.9
CONCLUSIONS 238
REFERENCES 238
PART MI
11 CENETIC TOXICITY: IN VITRO APPROACHES FOR HIT AND LEAD PROFLLING 243
RICHARD M WAIMSLEY AND NICHOIAS BILLINTON 11.1 INTRODUCTION 243
11.2 DEFINITIONS 245
11.3 MAJOR CHALLENGES FOR EARLY, PREDICTIVE GENOTOXICITY TESTING 246
11.4 PRACTICAL ISSUES FOR GENOTOXICITY PROFILING: VEHIDE, DOSE, DILUTION
RANGE AND IMPNRITY 248 11.4.1 VEHICLE AND DOSE 248
11.4.2 DILUTION RANGE 249 11.4.3 PURITY 249
11.5 COMPUTATIONAL APPROACHES TO GENOTOXICITY ASSESSMENT: "IN SILICO"
ASSESSMENT 250 11.5.1 HOW SHOULD IN SILICO METHODS BE APPLIED IN HIT AND
LEAD PROFILING? 252 11.6 GENOTOXICITY ASSAYS FOR SCREENING 253 11.6.1
GENE MUTATION ASSAYS 254
IMAGE 8
XII
CONTENTS
11 6.2 11.6.3 11.6.4 11
11
11
11 11 11
11 11 11
11 \\ 11 11
7 7.1 7.2 7.3 7.4 7.5 7.5.1 7.5.2 8
8.] 8.2
8.2.1 8.2.2
11.8.2.3 11 11 11
11 11
9 9.1 10 10.1
10.2
11.10.3 11 11
THE ARNES TEST AND VARIANTS 255 MAMMALIAN CELL MUTATION ASSAYS 256
SACCHAROMYCES CEREVISIAE ("YEAST"} MUTATION ASSAYS 256 CHROMOSOME DAMAGE
AND ABERRATION ASSAYS 256 ABERRATIONS 256 MICRONUCLEI 257
"COMET" ASSAY 258 DNA ADDUCT ASSESSMENT 25S GENE EXPRESSION ASSAYS 259
PROKARYOTIC 259
EUKARYOTIC 259 USING DATA FROM IN VITRO PROFILING: CONFIRMATORY TESTS,
FOLLOW-UP TESTS, AND THE LINK TO SAFETY ASSESSMENT AND IN VIVO MODELS
260 ANNOTATIONS FROM SCREENING DATA 261
ANNOTATION^ FROM POSITIVE SCREENING DATA 262 GENE MUTATION ASSAYS 262
CHROMOSOME DAMAGE ASSAYS 262 REPORTER ASSAYS 263 CAN A GENETIC TOXKITY
PROFILE INFORM IN VIVO TESTING STRATEGIES? 263
PROSPECTS FOR IN VIVO PROFILING OF HITS AND LEADS FOR GENOTOXICITY 264
WHAT TO TEST, WHEN AND HOW? 265 PROFILING ENTIRE LIBRARIES: 100 000
COMPOUNDS/YEAR 265
PROFILING HITS: 10 000-100 000 COMPOUNDS/YEAR 265 PROFILING IN LEAD
OPTIMIZATION: 2000-10 000 COMPOUNDS/YEAR 266 SUMMARY 267 REFERENCES 267
12 IN VITRO SAFETY PHARMACOLOGY PROFILING: AN IMPORTANT TOOL TO DECREASE
ATTRITION 273 JACQUES HOMON AND STEVEN WHITEBREAD WHAT IS "IN VITRO
SAFETY PHARMACOLOGY PROFILING?" 273
EXAMPLES OF DRUG FAILURES DUE TO SECONDARY PHARMACOLOGY 274 COMPONENTS
275 TARGET SELECTION 275 TARGET ANNOTATION 276
EXAMPLES OF IN VITRO SAFETY PHARMACOLOGY PROFILING PANELS 277 PROCESSES
280 ASSAY REQUIREMENTS AND TECHNOLOGIES 280 BINDING AND/OR FUNCTIONAL
ASSAYS 284
PROCESSES AND LOGISTICS 286 APPLICATION TO DRUG DISCOVERY 287 HOW AND
WHEN TO USE IN VITRO SAFETY PHARMACOLOGY
PROFILING 287 PHARMACOLOGICAL PROMISCUITY AND ITS CLINICAL
INTERPRETATION 288 RELEVANCE OF POTENCY AND THERAPEUTIC INDEX (TI) 290
12.1 12.2 12.2. 12.2. 12.2.
1 1.1 1.2
12.2.1.3 12.3 12.3 12.3 12.3 12.4
1 2 3
12.4.1
12.4 12.4 2 3
IMAGE 9
CONTENTS XIII
12.4.4 POSSIBLE BENEFITS OF OFF-TARGET EFFECTS 291
12.5 CONCLUSIONS AND OUTLOOK 291 REFERENCES 292
13 KNOWLEDGE-BASED AND COMPUTATIONAL APPROACHES TO IN VITRO SAFETY
PHARMACOLOGY 297
JOSEF SCHEIBER, ANDREAS BENDER, KOMOL AZZAOUI, ANDJEREMYJENKINS 13.1
INTRODUCTION 297
13.1.1 THE VALUE OF SAFETY PHARMACOLOGY DATA: THE VALUE AND RELEVANCE OF
COMPLETE, STANDARDIZED DATA MATRICES FOR IN SILICO PREDICTION OF ADVERSE
EVENTS 298
13.2 "META ANALYSIS" OF SAFETY PHARMACOLOGY DATA: PREDICTING COMPOUND
PROMISCUITY 304 13.2.1 INTRODUCTION 304 13.2.2 DATA ANALYSIS 305
13.2.2.1 HIT RATE PARAMETER AND CHEMICAL PROFILING 305
13.2.2.2 COMPUTATIONAL EFFORTS: GENERATION OF HYPOTHESES 307 13.2.2.3
PROMISCUITY AND ATTRITION RATE 308 13.2.2.4 CONCLUSION ON PROMISCUITY
PREDICTION 310
13.3 PREDICTION OF OFF-TARGET EFFECTS OF MOLECULES BASED ON CHEMICAL
STRUCTURE 310 13.3.1 INTRODUCTION 310 13.3.2 AVAILABLE DATABASES AND
DESIRED FORMAT 311 13.3.3 THE BEST ESTABLISHEDTECHNOLOGIES FOR IN
SUEICOTARGET FISHING 313 13.3.3.1 SIMILARIRY SEARCHING IN DATABASES 313
13.3.3.2 DATA MINING IN ANNOTATED CHEMICAL DATABASES 314 13.3.3.3 DATA
MINING ON BIOACRIVITY SPECTRA 314 13.4 FUTURE DIRECTIONS 316
REFERENCES 317
PART IV
14 DISCOVERY TOXICOLOGY SCREENING: PREDICTIVE, IN VITRO CYTOTOXICITY 325
PETERJ. O'BRIEN 14.1 INTRODUCTION 325
14.2 BASIS OF NEED FOR DISCOVERY TOXICOLOGY SCREENING 326 14.2.1 HIGH
ATTRITION AT HIGH COST 326 14.2.2 HIGH PROPORTION OF ATTRITION DUE TO
ADVERSE SAFETY 326 14.2.3 DISCOVERY SCREENING REDUCES ATTRITION BY AN
ORDER OF MAGNITUDE 326
14.3 OBSTADES TO DISCOVERY TOXICOLOGY SCREENING 327 14.4 NEED TO
COORDINATE CYTOTOXICITY SCREENING WITH OTHER DISCOVERY SAFETY
ASSESSMENTS 327 14.5 DISCOVERY CYTOTOXICOLOGY 329 14.5.1 BIOMARKCRS FOR
SAFETY VERSUS EFFICACY FOR SCREENING 329
IMAGE 10
XIV CONTENTS
14.5.2 PAST FAILURE OF CYTOTOXICITY ASSESSMENTS 329
14.5.2.1 INSUFFICIENT EXPOSURE 329 14.5.2.2 MEASUREMENT OF CELL DEATH
330 14.5.3 EFFECTIVE CELL-BASED ASSAYS FOR MARKED AND ACUTE CYTOTOXICITY
331 14.5.4 CHARACTERISTICS OF AN OPTIMALLY EFFECTIVE CELL MODEL OF
TOXICITY 331 14.5.4.1 NEED FOR MORPHOLOGICAL AND FUNCTIONAL PARAMETERS
333
14.5.4.2 NEED FOR MULTIPLE AND MECHANISTIC PARAMETERS 333 14.5.4.3 NEED
FOR SINGLE-CELL MONITORING 333 14.5.4.4 NEED FOR EFFECTIVE PARAMETERS
334 14.5.4.5 NEED FOR VALIDATION WITH HUMAN TOXICITY DATA 336 14.6 HIGH
EFFECTIVENESS OF AN HCA CELL MODEL IN PREDICTIVE TOXICOLOGY 337 14.6.1
BACKGROUND ON HCA 337 14.6.2 IDIOSYNCRATIC HEPATOTOXICITY 337 14.6.3
CHARACTERISTIC PATTERN AND SEQUENCE OF CYTOTOXIC CHANGES 338 14.6.4
SAFETY MARGIN 338 14.6.5 HORMESIS 338
14.6.6 IMPLEMENTATION OF HCA CYTOTOXICITY TESTING IN DRUG DISCOVERY 339
14.6.7 LIMITATIONS OF HCA CYTOTOXICITY TESTING IN DRUG DISCOVERY 340
14.7 FUTURE IMPACT OF CYTOTOXICITY TESTING 340 REFERENCES 341
15 PREDICTING DRUG-INDUCED HEPATOTOXICITY: IN VITRO, IN SILICO AND IN
VIVO APPROACHES 345 JINGHAIJ. XU, AMIT 5. KAIGUTKAR, YVONNE WILL, JAMES
DYKENS, ELIZABETH TENGSTRAND, AND FRANK HSIEH 15.1 INTRODUCTION 345
15.2 REACTIVE METABOLITES 346 15.2.1 ASSAYS AND IN SILICO KNOWLEDGE TO
ASSESS BIOACTIVATION POTENTIAL 347 15.2.1.1 IN VITRO REACTIVE METABOLITE
TRAPPING STUDIES 347 15.2.1.2 COVALENT BINDING DETERMINATIONS 348
15.2.2 UTILITY OF REACTIVE METABOLITE TRAPPING AND COVALENT BINDING
STUDIES IN DRUG DISCOVERY 348 15.2.3 ARE REACTIVE METABOLITE TRAPPING
AND COVALENT BINDING STUDIES RELIABLE PREDICTORS OF HEPATOTOXIC
POTENTIAL OF DRUG CANDIDATES? 348
15.2.4 MITIGATING FACTORS AGAINST HEPATOTOXICITY RISKS DUE TO
BIOACTIVATION - A BALANCED APPROACH TOWARDS CANDIDATE SELECTION IN DRUG
DISCOVERY 351 15.2.5 FUTURE DIRECTIONS 355 15.3 MITOCHONDRIAL TOXICITY
356 15.3.1 UNCOUPLERS OF MITOCHONDRIAL RESPIRATION 358 15.3.2 DRUGS THAT
INHIBIT OXPHOS COMPLEXES 358 15.3.3 DRUGS THAT INDUCE THE MITOCHONDRIAL
PERMEABUEITY TRANSITION PORE
(MPT) 359
15.3.4 DRUGS INHIBITING MTDNA SYNTHESIS AND MITOCHONDRIAL PROTEIN
SYNFHESIS 359 15.3.5 INHIBITION OF FATRY ACID SS-OXIDATION OR DEPLETION
OF COA 360
IMAGE 11
CONTENTS XV
15.3.6 IN VITRO AND IN VIVO ASSESSMENT OF DRUG-INDUCED MITOCHONDRIAL
DYSFUNCTION 360 OXIDATIVE STRESS 363 SOURCES OF OXIDATIVE STRESS 363
MEASUREMENTS OF OXIDATIVE STRESS 363 CRITICAL REVIEW: IS THERE
SUFFICIENT CLINICAL, PRE-CLINICAL AND
IN VITRO DATA TO SUBSTANTIATE THE LINK BETWEEN OXIDATIVE STRESS AND
IDIOSYNCRATIC IIVER INJURY? 364 INHIBITION OF BILE SALT EFFLUX PROTEIN
AND DRUG-INDUCED CHOLESTASIS 365 IN VITRO AND IN VIVO ASSAYS TO MEASURE
BSEP INHIBITION 365 CRITICAL REVIEW: IS THERE A LINK BETWEEN BSEP
INHIBITION, DRUG-INDUCED CHOLESTASIS AND IDIOSYNCRATIC IIVER INJURY? 368
BIOMARKERS 369 HEPATOCELLULAR INJURY 370 CHOLESTATIC INJURY 370
APPLICATION OF SERUM CHEMISTRY MARKERS 370
NEED FOR NEW BIOMARKERS 371 BIOMARKER DISCOVERY EFFORTS 372 APPROACHCS
FOR BIOMARKER DISCOVERY 372 DEVELOPMENT OF IN VIVO BIOMARKERS 373
DEVELOPMENT OF IN VITRO BIOMARKERS 373 BIOMARKER VALIDATION 374 FUTURE
BIOMARKER DIRECTIONS 374 CONCLUSIONS 375 REFERENCES 376
16 SHOULD CARDIOSAFETY BE RULED BY HERG INHIBITION? EARLY TESTING
SCENARIOS AND INTEGRATED RISK ASSESSMENT 387
DIMITRI MIKHAILOV, MARTIN TRAEBERT, QIANG LU, STEVEN WHITEBREOD, AND
WILLIAM EGAN 16.1 INTRODUCTION 387
16.2 ROLE OF ION CHANNELS IN HEART ELECTROPHYSIOLOGY 389 16.3 HERG
PROFILING ASSAYS 391 16.3.1 CELL-FREE COMPETITION BINDING ASSAYS 392
16.3.1.1 RADIOLIGAND BINDING 393 16.3.1.2 FLUORESCENCE POLARIZATION 393
16.3.2 NON-ELECTROPHYSIOLOGICAL FUNCTIONAL CELHILAR ASSAYS 393 16.3.2.1
RUBIDIUM EFFLUX AND THALLIUM INFLUX 393
16.3.2.2 MEMBRANE POTENTIAL-SENSITIVE FLUORESCENT DYES 394 16.3.3
HIGHER-THROUGHPUT PLANAR PATCH TECHNOLOGIES 394 16.3.4 NON-HERG ION
CHANNEL ASSAYS RELATED TO CARDIOTOXICITY 395 16.3.5 NONCLINICAL
CARDIOSAFETY ASSAYS IN EARLY DRUG DEVELOPMENT 396
16.4 COMPUTATIONAL MODELS FOR HERG 398 16.4.1 PHARMACOPHORE MODELS 398
16.4.2 DOCKING TO HOMOLOGY MODELS 399
15.4 15, 15 15
IS 15 15
15 15 15
15 15
4.1 4.2 4.3
5 5.1 5.2
6 6.1 6.') 6.3
6.4
15.6.5 15.6.6 15 15
15 15 15
6.6.1 6.6.2 6.6.3 .6.7 .7
IMAGE 12
XVI CONTENTS
16.4.3 QSAR MODELS 400
16.5 INTEGRATED RISK ASSESSMENT 401 16.5.1 CARDIOSAFETY ASSESSMENT OF
EARLY DISCOVERY PROJECTS 401 16.5.2 CARDIOSAFETY ASSESSMENT OF
PRECLINICAL POSITIVE SIGNALS 403 16.6 SUMMARY 405
REFERENCES 406
17 HEMATOTOXICITY: IN VITRO AND EX VIVO COMPOUND PROFILING 415 DAVID
BROTT AND FRANCOIS POGNAN 17.1 INTRODUCTION 415
17.2 KNOWN COMPOUNDS WITH HEMATOTOXIC POTENTIAL 417 17.3 TIERED CASCADE
OFTESTING 419 17.3.1 TIER 1 TESTS 420
17.3.2 TIER 2 TESTS 426
17.3.3 TIER 3 TESTS 428
17.4 TRIGGERS FOR HEMATOTOXICITY TESTING 430 17.5 CONCLUSIONS 433
REFERENCES 433
18 PROFILING ADVERSE IMMUNE EFFECTS 439 WIM H. DEJONG, ROYMOND PIETERS,
KIRSTEN A BAKEN, ROBJ. VANDEBRIEL, JAN-WILLEM VAN DER LAAN, AND HENK VAN
LODEREN 18.1 IMMUNOTOXICOLOGY 439
18.1.1 THE IMMUNE SYSTEM AND IMMUNOTOXICOLOGY 439 18.1.2 DETECTION OF
IMMUNOTOXICITY 442 18.1.3 EVALUATION OF THE IMMUNE SYSTEM IN TOXICITY
STUDIES 443 18.1.4 TESTING FOR INDUCTION OF ALLERGY 445
18.1.5 TESTING FOR INDUCTION OF AUTOIMMUNITY 446 18.1.5.1 INTRODUCTION
446 18.1.5.2 ASSAYS FOR TESTING THE INDUCTION OF AUTOIMMUNITY 446
18.1.5.3 ALTERNATIVE APPROACH FOR EVALUATION OF AUTOIMMUNITY POTENTIAL
OF CHEMICALS 447
18.1.6 STRUCTURES ASSOCIATED WITH IMMUNOTOXIDTY 449 18.1.7
IMMUNOSTIMULATION BY COMPONENTS OF THE IMMUNE SYSTEMS USED AS
THERAPEUTICS 450 18.2 NON-ANIMAL APPROACHES FOR THE DETERMINATION OF
IMMUNOTOXICIT)' 451 18.2.1 IN SILICO APPROACHES 451 18.2.2 IN VITRO
APPROACHES TO TEST VARIOUS ASPECTS OF IMMUNOTOXICIT)' 451 18.2.2.1
INTRODUCTION 451 18.2.2.2 IMMUNOSUPPRESSION 453 18.2.2.3 CHEMICAL
SENSITIZATION 454 18.2.2.4 CONCLUSIONS 456 18.2.3 TOXICOGENOMICS 456
18.2.3.1 INTRODUCTION 456 18.2.3.2 IMMUNOTOXICOGENOMICS 456
IMAGE 13
CONTENTS XVII
18.2.3.3 INTERPRETATION OF RESULTS 457
18-2.3.4 TOXICOGENOMICS FOR PREDICTION OF EFFECTS 457 18.2.3.5 TARGET
ORGANS AND CELLS FOR IMMUNOTOXICITY 458 18.2.3.6 CONCLUSIONS 458 18.3
SUMMARY 459
REFERENCES 459
19 IN VITRO PHOTOTOXICITY TESTING: A PROCEDURE INVOLVING MULTIPLE
ENDPOTNTS 471 LAURENT MARROT ANDJEAN-ROCH MEUNIER
19.1 TNTRODUCTION 471
19.2 OPTICAL CONSIDERATIONS: RELEVANT UV SOURCES AND SUNLIGHT ABSORPTION
472 19.2.1 WORKING WITH THE APPROPRIATE ARTIFICIAL SUNLIGHT SOURCE
DETCRMINES THE RELEVANCE OF PHOTOTOXICITY SCREENING 472 19.2.2 WHEN TO
STUDY THE PHOTOTOXICITY OF A SUBSTANCE? 474 19.3 IN SILICO METHODS FOR
PREDICTION OF PHOTOTOXICITY - (Q)SAR MODELS 474
19.3.1 GLOBAL MODELS 475 19.3.2 LOCAL MODELS 475 19.4 PBOTOREACTIVITY IN
TUBO: PRESCREENING OF COMPOUNDS PRODUCING ROS UPON SUNLIGHT EXPOSURE 478
19.4.1. BIOCHEMICAL DETECTION OF PHOTOINDUCED ROS 478 19.4.2
PHOTO-CLEAVAGE OF ISOLATED PLASMID DNA 479 19.4.3 PHOTO RED BLOOD CELLS
TEST 479 19.5 MICROBIOLOGICAL MODELS FOR PHOTOMUTAGENESIS ASSESSMENT 480
19.5.1 PHOTO-AMES TEST 480 19.5.2 THE YEAST MODEL 480 19.6
PHOTOCYTOTOXICITY AND PHOTOGENOTOXIDTY IN MAMMALIAN CELLS: REGULATORY
TESTS AND BEYOND 4S2
19.6.1 THE 3T3 NRU ASSAY: A VALIDATED TEST FOR THE ASSESSMENT OF A
PHOTOIRRITATION POTENTIAL 482 19.6.2 PHOTOGENOTOXICITY: AN ENDPOINT
WITHOUT CORRESPONDING IN VIVO EQUIVALENTS 483 19.7 RECONSTRUCTED SKIN: A
MODEL FOR MIMICKING PHOTOTOXICITY IN THE
TARGET ORGAN 486
19.8 CONCLUSIONS 488
REFERENCES 489
INDEX 495 |
| any_adam_object | 1 |
| author2 | Faller, Bernard Urbán, László |
| author2_role | edt edt |
| author2_variant | b f bf l u lu |
| author_GND | (DE-588)139068589 |
| author_facet | Faller, Bernard Urbán, László |
| building | Verbundindex |
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| dewey-full | 615.19 |
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| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.19 |
| dewey-search | 615.19 |
| dewey-sort | 3615.19 |
| dewey-tens | 610 - Medicine and health |
| discipline | Chemie / Pharmazie Medizin |
| format | Book |
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| id | DE-604.BV035725829 |
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| indexdate | 2024-07-20T10:19:11Z |
| institution | BVB |
| isbn | 9783527323319 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-018002522 |
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| physical | XXX, 503 S. Ill., graph. Darst. 240 mm x 170 mm |
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| series | Methods and Principles in Medicinal Chemistry |
| series2 | Methods and Principles in Medicinal Chemistry |
| spelling | Hit and lead profiling identification and optimization of drug-like molecules ed. by Bernard Faller ... Weinheim, Bergstr Wiley-VCH Verlag GmbH & Co. KGaA 2009 XXX, 503 S. Ill., graph. Darst. 240 mm x 170 mm txt rdacontent n rdamedia nc rdacarrier Methods and Principles in Medicinal Chemistry 43 Arzneimittelentwicklung - Aufsatzsammlung Arzneimittelentwicklung (DE-588)4143176-5 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Arzneimittelentwicklung (DE-588)4143176-5 s DE-604 Faller, Bernard (DE-588)139068589 edt Urbán, László edt Methods and Principles in Medicinal Chemistry 43 (DE-604)BV035418617 43 text/html http://deposit.dnb.de/cgi-bin/dokserv?id=3243353&prov=M&dok_var=1&dok_ext=htm Inhaltstext OEBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=018002522&sequence=000003&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Hit and lead profiling identification and optimization of drug-like molecules Methods and Principles in Medicinal Chemistry Arzneimittelentwicklung - Aufsatzsammlung Arzneimittelentwicklung (DE-588)4143176-5 gnd |
| subject_GND | (DE-588)4143176-5 (DE-588)4143413-4 |
| title | Hit and lead profiling identification and optimization of drug-like molecules |
| title_auth | Hit and lead profiling identification and optimization of drug-like molecules |
| title_exact_search | Hit and lead profiling identification and optimization of drug-like molecules |
| title_full | Hit and lead profiling identification and optimization of drug-like molecules ed. by Bernard Faller ... |
| title_fullStr | Hit and lead profiling identification and optimization of drug-like molecules ed. by Bernard Faller ... |
| title_full_unstemmed | Hit and lead profiling identification and optimization of drug-like molecules ed. by Bernard Faller ... |
| title_short | Hit and lead profiling |
| title_sort | hit and lead profiling identification and optimization of drug like molecules |
| title_sub | identification and optimization of drug-like molecules |
| topic | Arzneimittelentwicklung - Aufsatzsammlung Arzneimittelentwicklung (DE-588)4143176-5 gnd |
| topic_facet | Arzneimittelentwicklung - Aufsatzsammlung Arzneimittelentwicklung Aufsatzsammlung |
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