Real world drug discovery: a chemistś guide to biotech and pharmaceutical research
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Amsterdam [u.a.]
Elsevier
2008
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| Online-Zugang: | Inhaltsverzeichnis Inhaltsverzeichnis |
| Beschreibung: | Literaturangaben |
| Beschreibung: | XVII, 515 S. Ill., graph. Darst. |
| ISBN: | 9780080466170 |
Internformat
MARC
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| 020 | |a 9780080466170 |9 978-0-08-046617-0 | ||
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| 100 | 1 | |a Rydzewski, Robert M. |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a Real world drug discovery |b a chemistś guide to biotech and pharmaceutical research |c Robert M. Rydzewski |
| 264 | 1 | |a Amsterdam [u.a.] |b Elsevier |c 2008 | |
| 300 | |a XVII, 515 S. |b Ill., graph. Darst. | ||
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| 500 | |a Literaturangaben | ||
| 856 | 4 | |u http://www.gbv.de/dms/bs/toc/566443651.pdf |3 Inhaltsverzeichnis | |
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Datensatz im Suchindex
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|---|---|
| adam_text | IMAGE 1
REAL WORLD DRUG DISCOVERY
A CHEMIST S GUIDE TO BIOTECH AND PHARMACEUTICAL RESEARCH
ROBERT M. RYDZEWSKI
ELSEVIER
AMSTERDAM * BOSTON * HEIDELBERG * LONDON * NEW YORK * OXFORD PARIS * SAN
DIEGO * SAN FRANCISCO * SINGAPORE * SYDNEY * TOKYO
IMAGE 2
CONTENTS
PREFACE XII
ACKNOWLEDGEMENTS XVI
ABOUT THE AUTHOR XVIII
1 THE DRUG DISCOVERY BUSINESS TO DATE 1
1. 1 INTRODUCTION 1
1.2 THE PAST 2
1.2.1 PHARMA ROOTS 2
1.2.2 BIOTECH IS BORN 6
1.2.3 THE GENOMICS REVOLUTION 9
1.3 CURRENT ECONOMICS-PROBLEMS 13
1.3.1 COST OF DRUG DEVELOPMENT 14
1.3.2 THE PRODUCTIVITY GAP 16
1.3.3 MARKET WITHDRAWALS 19
1.3.4 GENERIC COMPETITION 21
1.4 CURRENT ECONOMICS-SOLUTIONS 26
1.4.1 PHARMA PROFITS AND MARKET EXPANSION 26
1.4.2 MERGERS AND ACQUISITIONS 28
1.4.3 BIOTECH CLINICAL CANDIDATES TO PHARMA 29
1.4.4 ACADEMIC CONTRIBUTIONS 31
1.4.5 GLOBAL OUTSOURCING 32
1.4.6 BLOCKBUSTERS AND ORPHAN DRUGS 39
1.4.7 REPURPOSING 40
1.4.8 CHIRAL SWITCHING 42
1.4.9 COMBINATION THERAPEUTICS 44
1.4.10 REFORMULATION 45
1.5 SUMMARY 46
IMAGE 3
THE
2.1 2.2
2.3
2.4
DRUG DISCOVERY BUSINESS TO COME INTRODUCTION NEW 2.2.1 2.2.2 2.2.3 2.2.4
2.2.5 NEW 2.3.1
2.3.2 2.3.3 2.3.4
2.3.5 NEW 2.4.1 2.4.2
2.4.3 2.4.4 2.4.5
2.4.6
MODELS FOR PHARMA R&D MINUS R D PLUS R SMALLER IS BETTER SPECIALTY DRUGS
PRICING PRESSURES AND PRICE CONTROLS MODELS FOR ACADEMIA AND BIOTECH
TRANSLATIONAL RESEARCH THE STANDARD BIOTECH MODEL IS IT A PROJECT OR A
COMPANY? LEANER, MEANER START-UPS
BIOTECH ALTERNATIVES TECHNOLOGIES S-CURVES AND EXPECTATIONS
GENOMICS REDUX PERSONALIZED MEDICINE PHARMACOGENOMICS OTHER OMICS
THE ADOPTION OF PERSONALIZED MEDICINE
VIII CONTENTS
53
53 53 53 56
58 60 60 65
65 68 72 74 75 80
80 85 88 89 98 102
2.5 SUMMARY 104
3 INDUSTRIAL CONSIDERATIONS 113
3.1 INTELLECTUAL PROPERTY 113
3.1.1 THE VALUE OF NEW IDEAS 113
3.1.2 PATENTS 118
3.2 OUTSIDE RESOURCES 132
3.2.1 CONSULTANTS 132
3.2.2 ACADEMIC OR GOVERNMENT RESEARCH AGREEMENTS 136
3.2.3 BIG COMPANY-SMALL COMPANY COLLABORATIONS 138
3.3 THE NEW DRUG R&D PROCESS 141
3.3.1 TARGET IDENTIFICATION 141
3.3.2 LEAD IDENTIFICATION 143
3.3.3 LEAD OPTIMIZATION 143
3.3.4 PRECLINICAL 144
3.3.5 STAGES IN CLINICAL DEVELOPMENT 146
3.3.6 WHAT ARE THE ODDS? 147
4 HOW THINGS GET DONE: THE PROJECT TEAM 151
4.1 INTRODUCTION 151
4.2 THE PROJECT TEAM 152
4.2.1 THE PROJECT GOAL 152
4.2.2 PROJECT TEAM ORGANIZATION 155
4.2.3 PROJECT TEAM MEETINGS 164
IMAGE 4
CONTENTS JX
4.3 CONCLUSIONS 171
4.3.1 SUMMING U P . .. 171
4.3.2 IS IT REALLY BEST? 172
4.3.3 THE BENEFITS 173
5 PROJECT CONSIDERATIONS 175
5.1 INTRODUCTION 175
5.2 ESTABLISHED TARGETS 176
5.3 ESTABLISHED TOUGH TARGETS 182
5.4 NOVEL TARGETS 183
5.4.1 IDENTIFYING NEW TARGETS 183
5.4.2 TARGET VALIDATION 185
5.4.3 WORKING ON NOVEL TARGET-DIRECTED PROJECTS 195
5.5 TARGETS ARISING FROM PHENOTYPE OR HIGH-CONTENT SCREENING 200
5.5.1 PHENOTYPE SCREENING VERSUS TARGET SCREENING 200
5.5.2 ELUCIDATION OF PHENOTYPE-DERIVED TARGETS 206
5.6 IN CONCLUSION 212
6 HIT GENERATION 218
6.1 INTRODUCTION 218
6.2 DEFINITIONS 218
6.3 GROUPS INVOLVED IN HIT-TO-LEAD 220
6.4 HIGH-THROUGHPUT SCREENING 221
6.4.1 HISTORY 221
6.4.2 MYTHS AND TRUTHS ABOUT HTS 222
6.5 APPROACHES TO HIT GENERATION 240
6.5.1 RANDOM OR NON-DIRECTED METHODS 240
6.5.2 SCREENING OF SYNTHETIC COMPOUND COLLECTIONS 241
6.5.3 SCREENING OF COMBINATORIAL DIVERSITY LIBRARIES 244
6.5.4 FRAGMENT SCREENING 248
6.5.5 SCREENING OF NATURAL PRODUCTS AND DOS LIBRARIES 257
6.5.6 DIRECTED OR KNOWLEDGE-BASED METHODS 262
7 TURNING HITS INTO DRUGS 280
7.1 WHAT NOW? 280
7.2 BIOCHEMICAL MECHANISM IN HIT SELECTION 281
7.2.1 COMPETITION AND ALLOSTERY 281
7.2.2 IRREVERSIBILITY 285
7.2.3 SLOW OFF-RATE COMPOUNDS 286
7.2.4 WHY MECHANISM MATTERS 288
7.3 DRUGLIKENESS 289
7.3.1 WHAT IS IT? 289
7.3.2 PREDICTING DRUGLIKENESS 290
7.4 MULTIDIMENSIONAL OPTIMIZATION 293
IMAGE 5
CONTENTS
7.5 LEAD OPTIMIZATION VERSUS HTL 295
7.6 USING STRUCTURE-BASED DRUG DESIGN 296
7.6.1 DEFINITION, HISTORY, AND GOALS 296
7.6.2 POTENTIAL LIMITATIONS 299
7.6.3 EXAMPLES 302
7.6.4 WORKING WITH MODELERS 307
7.6.5 CONCLUSIONS 308
INITIAL PROPERTIES 313
8.1 WHY NOT ALL AT ONCE? 313
8.2 POTENCY 313
8.2.1 WHAT, WHY, AND HOW MUCH? 313
8.2.2 SPECIES SPECIFICITY 315
8.3 SELECTIVITY 317
8.3.1 SELECTIVITY... NOT! 317
8.3.2 ANTITARGETS 320
8.4 STRUCTURAL NOVELTY 323
8.4.1 BIOISOSTERES, GROUP, AND ATOM REPLACEMENTS 323
8.4.2 SCAFFOLD HOPPING, MORPHING, AND GRAFTING 328
8.4.3 CYCLIZATION AND RING OPENING 331
8.4.4 OTHER METHODS 333
8.5 SOLUBILITY 335
8.5.1 DEFINING, ESTIMATING, AND MEASURING SOLUBILITY 335
8.5.2 PROBLEMS RESULTING FROM POOR SOLUBILITY 335
8.5.3 IMPROVING SOLUBILITY 337
8.6 CHEMICAL AND PLASMA STABILITY 340
8.6.1 DEFINITIONS AND IMPORTANCE 340
8.6.2 COMMON TYPES OF INSTABILITY 341
ADME AND PK PROPERTIES 353
9.1 CELL PERMEABILITY AND ABSORPTION 353
9.1.1 DEFINITIONS 353
9.1.2 A CLOSER LOOK AT INTESTINAL ABSORPTION 355
9.1.3 MODELS OF CELL PERMEABILITY AND ABSORPTION 358
9.1.4 IMPROVING CELL PERMEABILITY AND ABSORPTION 369
9.2 METABOLIC STABILITY 374
9.2.1 COMMON METABOLIC TRANSFORMATIONS 375
9.2.2 ASSESSING METABOLIC STABILITY 382
9.2.3 IMPROVING METABOLIC STABILITY 385
9.3 PLASMA PROTEIN BINDING 392
9.3.1 IS IT IMPORTANT? 392
9.3.2 MEASURING PLASMA PROTEIN BINDING 396
9.3.3 MINIMIZING PLASMA PROTEIN BINDING 398
IMAGE 6
CONTENTS XI
9.4 P-GLYCOPROTEIN INTERACTIONS 401
9.4.1 STRUCTURE AND FUNCTION 401
9.4.2 TYPES OF P-GP INTERACTIONS 404
9.4.3 MEASURING P-GP INTERACTIONS 405
9.4.4 REDUCING P-GP INTERACTIONS 408
9.5 BIOAVAILABILITY 411
9.5.1 INTRODUCTION 411
9.5.2 UNDERSTANDING AND OVERCOMING POOR ORAL BIOAVAILABILITY 413 9.5.3
THINGS TO KEEP IN MIND 418
10 TOXICITY-RELATED PROPERTIES 430
10.1 CYP INHIBITION 430
10.1.1 IMPORTANCE 430
10.1.2 TYPES OF CYP INHIBITION 432
10.1.3 CYP INHIBITION ASSAYS 434
10.1.4 COMMON STRUCTURAL FEATURES OF CYP INHIBITORS 438
10.1.5 WAYS TO REDUCE CYP INHIBITION 441
10.2 CYP INDUCTION 445
10.3 BINDING TO THE HERG RECEPTOR 450
10.3.1 INTRODUCTION 450
10.3.2 IN VITRO ASSAYS 451
10.3.3 MODELS OF HERG BINDING 452
10.3.4 REDUCING HERG INTERACTIONS 454
10.4 MUTAGENICITY 457
10.4.1 BACKGROUND 457
10.4.2 STRUCTURAL ASPECTS 460
11 A CAREER IN DRUG DISCOVERY RESEARCH 469
11.1 HIRING: A GOOD MATCH 469
11.1.1 WHAT DO EMPLOYERS WANT? 469
11.1.2 WHAT SHOULD A CANDIDATE LOOK FOR? 474
11.2 ASSESSING PERFORMANCE 482
11.2.1 EVALUATIONS 482
11.2.2 PROMOTIONS 484
11.3 THE LONG HAUL: PERSPECTIVES 485
11.3.1 JOB AND INDUSTRY EVOLUTION 486
11.3.2 THE EVOLUTION OF A RESEARCH CAREER 487
* 1.3.3 FRUSTRATION 489
11.3.4 HOPE 490
APPENDIX BEST-SELLING SMALL MOLECULE SINGLE AGENT PRESCRIPTION DRUGS:
THE PERIODIC TABLE OF DRUGS 2006 495
INDEX 499
|
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| spelling | Rydzewski, Robert M. Verfasser aut Real world drug discovery a chemistś guide to biotech and pharmaceutical research Robert M. Rydzewski Amsterdam [u.a.] Elsevier 2008 XVII, 515 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Literaturangaben http://www.gbv.de/dms/bs/toc/566443651.pdf Inhaltsverzeichnis GBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=022298802&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Rydzewski, Robert M. Real world drug discovery a chemistś guide to biotech and pharmaceutical research |
| title | Real world drug discovery a chemistś guide to biotech and pharmaceutical research |
| title_auth | Real world drug discovery a chemistś guide to biotech and pharmaceutical research |
| title_exact_search | Real world drug discovery a chemistś guide to biotech and pharmaceutical research |
| title_full | Real world drug discovery a chemistś guide to biotech and pharmaceutical research Robert M. Rydzewski |
| title_fullStr | Real world drug discovery a chemistś guide to biotech and pharmaceutical research Robert M. Rydzewski |
| title_full_unstemmed | Real world drug discovery a chemistś guide to biotech and pharmaceutical research Robert M. Rydzewski |
| title_short | Real world drug discovery |
| title_sort | real world drug discovery a chemists guide to biotech and pharmaceutical research |
| title_sub | a chemistś guide to biotech and pharmaceutical research |
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