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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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This book is a reflection of today's knowledge in drug metabolism and pharmacokinetics. However, there is more to come, when in the future the role and function of various transporters is better understood and predictive methods have matured further.
As series editors we would like to thank the authors for their efforts in bringing this book to completion. No doubt the rich experience of the authors expressed in
X | Preface
this volume will be of great value to many medicinal chemists, experienced or junior, and this volume will be a treasure in many laboratories engaged in the synthesis of drugs.
Last, but not least we wish to express our gratitude to Gudrun Walter and Frank Weinreich from Wiley-VCH publishers for the fruitful collaboration.
April 2001
Raimund Mannhold, Dusseldorf Hugo Kubinyi, Ludwigshafen Henk Timmerman, Amsterdam
Pharmacokinetics and Metabolism in Drug Design XI Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)
A Personal Foreword
The concept of this book is simple. It represents the distillation of my experiences over 25 years within Drug Discovery and Drug Development and particularly how the science of Drug Metabolism and Pharmacokinetics impacts upon Medicinal Chemistry. Hopefully it will be a source of some knowledge, but more importantly, a stimulus for medicinal chemists to want to understand as much as possible about the chemicals they make. As the work grew I realized it was impossible to fulfil the concept of this book without involving others. I am extremely grateful to my co-authors Don Walker and Han van de Waterbeemd for helping turn a skeleton into a fully clothed body, and in the process contributing a large number of new ideas and directions. Upon completion of the book I realize how little we know and how much there is to do. Medicinal chemists often refer to the ‘magic methyl’. This term covers the small synthetic addition, which almost magically solves a Discovery problem, transforming a mere ligand into a potential drug, beyond the scope of existing struc-ture-activity relationships. A single methyl can disrupt crystal lattices, break hydration spheres, modulate metabolism, enhance chemical stability, displace water in a binding site and turns the sometimes weary predictable plod of methyl, ethyl, propyl, futile into methyl, ethyl, another methyl magic! This book has no magical secrets unfortunately, but time and time again the logical search for solutions is eventually rewarded by unexpected gains.
Sandwich, June 2001
Dennis A. Smith
Pharmacokinetics and Metabolism in Drug Design 143 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)
Index
a
absorption 35, 64, 71, 137 absorption potential 44 absorption window 38 accumulation ratio 24 acetaminophen 105 acetanilide 107 acidic drugs 126 actin 48
active secretion 67 active site 77 topography 77 active transport 67, 69 ADME criteria 134 ADME screens 133 affinity constant 25 age 71,124 agonist 26
agranulocytosis 104, 105, 111, 112, 119 albumin 48 alcohol 91, 94 alfentanil 3
alkylating compounds 93 allometric exponent 125 allometric relationship 130 allometric scaling 124, 129 allometry 129 amiodarone 101 amlodipine 17, 53, 54 amodiaquine 104 anilino function 108 animal models 116 animal test 99 antagonist 26 anti-allergy agents 102 antiarrhythmic drugs 109 antiarrhythmic 55 anticholinergics 89 anti-diabetic 107 antihypertensive 95
anti-inflammatory agent 113 antimalarial 104 antimuscarinic compounds 87 antipyrine 128 aplastic anaemia 103, 111 aqueous channels 28, 29 hydrophilic compounds 29 aqueous pore 47, 64 aqueous pores (tight junctions) 38 atenolol 27, 50, 51, 64, 107 azithromycin 54
b
p1/p2 selectivity 51 p2-adrenergic receptor 30 P-adrenoceptor antagonists 39, 64 P-adrenoceptor blockers 86 benzoquinone 104 benzylic hydroxylation 83 benzylic positions 83 beta-adrenoceptor antagonist 42 betaxolol 42, 79 biliary cannaliculus 102 biliary clearance 60 biliary excretion 60, 130 bioavailability 22, 23, 41, 42 bioisosteres 94 biophase 27 blood dyscrasias 114 blood flow 126
blood-brain barrier 27, 28, 29, 50, 71 body weight 124 bosentan 129 brain weight 128
c
caco-2 44 caco-2 cells 43 caco-2 monolayers 3, 137 calcium channel blockers 54
144 | Index
candoxatril 89 candoxatrilat 89 captopril 88
carbamazepine 50, 103, 118
carboxylic acid 90
carbutamide 107
carcinogenesis 102
carfentanil 30
cassette dosing 137
catechol methyl transferases 95
catechols 92
celecoxib 83
celiprolol 43
cell death 102
chloroquinoline 114
chlorphentermine 11
chlorpropamide 80
cholesterol absorption inhibitor 83, 85
cholinesterase inhibitor 62
chromone 102
cimetidine 3, 68, 114
cisplatin 116
class III antidysrhythmic agents 69 clearance 17, 32, 59, 126, 138 AUC 19 free drug 18 high clearance drugs 19 instrinsic clearance 18 intrinsic clearance 19 low clearance drugs 19 organs of extraction 18 systemic clearance 18 unbound clearance 19 cloned receptors 134 clozapine 109, 119 CNS 28, 47, 48, 49, 50 CNS uptake 7 Alog D 7 Alog P 7 zwitterions 7 co-administered drugs 117 cocktail dosing 137 codeine 55 collecting tubule 67 combinatorial chemistry 133 co-medications 124 computational systems 135 creatinine clearance 127 creatinine 71 cromakalim 86 crystal packing 36 CSF 49
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