TF1766_half 7/22/04 2:52 PM Page 1 Enzymes and Their Inhibition Drug Development © 2005 by CRC Press TF1766_series 10/4/04 2:24 PM Page 1 Series Editors H. John Smith and Claire Simons Cardiff Univeristy Cardiff, UK CRC Enzyme Inhibitors Series Carbonic Anhydrase: Its Inhibitors and Activators Edited by Claudiu T. Supuran, Andrea Scozzafava and Janet Conway Enzymes and Their Inhibitors: Drug Development Edited by H. John Smith and Claire Simons © 2005 by CRC Press TF1766_title 7/22/04 2:53 PM Page 1 CRC PRESS Boca Raton London New York Washington, D.C. CRC Enzyme Inhibitors Series Enzymes and Their Inhibition Drug Development Edited by H. John Smith and Claire Simons © 2005 by CRC Press This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. 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John Smith and Claire Simons. p.; cm. — (Enzyme inhibitor) Includes bibliographical references and index. ISBN 0-415-33402-0 (alk. paper) 1. Enzyme inhibitors. 2. Drug development. I. Smith, H. J., 1930- II. Simons, Claire. III. CRC enzyme inhibitors series. [DNLM: 1. Enzyme Inhibitors. 2. Chemistry, Pharmaceutical. 3. Drug Design. QU 143 E6154 2004] QP601.5.E5945 2004 615 ¢ .35—dc22 2004055375 TF1766_C000.fm Page 4 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press Series Preface One approach to the development of drugs as medicines, which has gained consid- erable success over the past two decades, involves inhibition of the activity of a target enzyme in the body or invading parasite by a small molecule inhibitor, leading to a useful clinical effect. The CRC Enzyme Inhibitor Series consists of an expanding series of monographs on this aspect of drug development, providing timely and in-depth accounts of developing and future targets that collectively embrace the contributions of medicinal chemistry (synthesis, design), pharmacology and toxicology, biochemistry, physiol- ogy, and biopharmaceutics necessary in the development of novel pharmaceutics. H. John Smith Claire Simons TF1766_C000.fm Page 5 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press Preface The majority of drugs used clinically exert their action in one of two ways: (1) by interfering with a component (agonist) in the body, preventing interaction with its site of action (receptor), i.e., receptor antagonist, or (2) by interfering with an enzyme normally essential for the well-being of the body or involved in bacterial or parasitic or fungal growth causing disease and infectious states, where the removal of its activity by treatment is necessary, i.e., enzyme inhibitors . In recent years the pro- portion of current drugs described as enzyme inhibitors has increased, and this book gives an account of the steps taken for designing and developing such inhibitors — from identification of the target enzyme to be blocked in a particular disease or infection to their introduction in the marketplace. Once the enzyme target is selected or discovered, a knowledge of the structure, substrates, kinetics, and mechanism of the enzyme can be brought together in the rational design of an inhibitor. However, the transfer of a prospective drug candidate from the laboratory bench to the marketplace follows a prolonged and difficult pathway due to the body’s requirements for suitable absorption, distribution, metab- olism, and selectivity characteristics so as to arrive at its site of action at a satisfactory concentration level devoid of unnecessary side effects. TF1766_C000.fm Page 7 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press Editors H. John Smith is a former reader in medicinal chemistry at the Welsh School of Pharmacy, Cardiff University, U.K. He obtained his Ph.D. in medicinal chemistry at the University of London and received his D.Sc. in 1995. A fellow of the Royal Society of Chemistry and the Royal Pharmaceutical Society of Great Britain, he has spent much of his career studying enzyme inhibitors and their potential use in drugs. John Smith has coauthored several texts on this subject and is editor-in-chief of the Journal of Enzyme Inhibition and Medicinal Chemistry . Claire Simons is a lecturer in medicinal chemistry at the Welsh School of Pharmacy, Cardiff University, U.K. She obtained her Ph.D. in organic chemistry at King’s College, University of London, and is a member of the Royal Society of Chemistry. Her main research interests are the design, synthesis, and computational analysis of novel heterocyclic and nucleoside compounds as enzyme inhibitors. Claire Simons has authored a textbook on nucleoside chemistry and its therapeutic application and coedited (with John Smith) a textbook, Proteinase and Peptidase Inhibition . TF1766_C000.fm Page 9 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press Contributors Paul J. Ala Incyte Corporation Wilmington, Delaware Anthony J. Berdis Department of Pharmacology Case Western Reserve University Cleveland, Ohio Angela Casini Department of Chemistry University of Florence Florence, Italy Chong-Hwan Chang Bristol-Myers Squibb Company Princeton, New Jersey Hans-Ulrich Demuth Probiodrug Research Ltd Weinbergweg Research Ltd Halle, Germany Samer Haidar Faculty of Pharmaceutical and Medicinal Chemistry University of the Saar Saarbrucken, Germany Rolf W. Hartmann Faculty of Pharmaceutical and Medicinal Chemistry University of the Saar Saarbrucken, Germany Neil R. Kitteringham Department of Pharmacology and Therapeutics University of Liverpool Liverpool, United Kingdom Irene Lee Department of Chemistry Case Western Reserve University Cleveland, Ohio W. Edward Lindup Department of Pharmacology and Therapeutics University of Liverpool Liverpool, United Kingdom Edward A. Meighen Department of Biochemistry McGill University Montreal, Quebec, Canada André J. Neistroj Probiodrug Research Ltd Weinbergweg Research Ltd Halle, Germany Bruce A. Palfey Department of Biological Chemistry University of Michigan Medical School Ann Arbor, Michigan Andrea Scozzafava Department of Chemistry University of Florence Florence, Italy TF1766_C000.fm Page 11 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press Claire Simons Welsh School of Pharmacy Cardiff University Cardiff, United Kingdom H. John Smith Welsh School of Pharmacy Cardiff University Cardiff, United Kingdom Torsten Steinmetzer Curacyte Chemistry GmbH Jena, Germany Jure Stojan Institute of Biochemistry University of Ljubljana Ljubljana, Slovenia Claudiu T. Supuran Department of Chemistry University of Florence Florence, Italy L.W. Lawrence Woo Department of Pharmacy and Pharmacology University of Bath Bath, United Kingdom TF1766_C000.fm Page 12 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press Abbreviations AADC amino acid decarboxylase ACE angiotensin 1 converting enzyme Adiol androstenediol ADP adenosine diphosphate AFM atomic force microscope AG aminoglutethimide AhR Ah receptor AMP adenosine monophosphate ARNT Ah receptor nuclear transporter ASA/ASB aryl sulfatase A/B ATCase aspartate transcarbamylase ATP adenosine triphosphate BOC tert -butoxycabonyl BPH benign prostatic hyperplasia CA carbonic anhydrase CAR constitutive androstane receptor CD circular dichroism ChC Clostridium hydrolyticum collagenase CoA coenzyme A CoMFA comparative molecular field analysis COMT catechol- O -methyltransferase CYP 17 17 a -hydrolyase/C17-20-lyase CYP 19 aromatase DHEA dehydroepiandrosterone DHPS dihydropteroate synthase DHT dihydrotestosterone DIQ decahydroisoquinoline DOPA L-3,4-dihydroxyphenyl alanine DPIV dipeptidyl peptidase IV DTT dithiothreitol E1 estrone E2 estradiol E1S estrone sulfate ECM extracellular matrix EMATE estrone-3- O -sulfamate FAD flavine adenine dinucleotide FGly formylglycine FMN flavine mononucleotide DD DD G free energy change GABA a -aminobutyric acid TF1766_C000.fm Page 13 Tuesday, October 12, 2004 4:08 PM © 2005 by CRC Press [...]... 4:10 PM Contents Chapter 1 Enzyme Structure and Function Edward A Meighen Chapter 2 Mechanisms Bruce A Palfey 2.5 Cytochrome P450 Example W Edward Lindup and Neil R Kitteringham 2.6 Carbonic Anhydrase Example Claudiu T Supuran, Andrea Scozzafava, and Angela Casini 2.7 Proteases Example André J Niestroj and Hans-Ulrich Demuth Chapter 3 Kinetics Irene Lee and Anthony J Berdis Chapter 4 Enzyme Inhibitors... and Claire Simons 5.6 Enzyme Inhibitor Examples for the Treatment of Breast Cancer L.W Lawrence Woo 5.7 Enzyme Inhibitor Examples for the Treatment of Prostate Tumor Samer Haidar and Rolf W Hartmann 5.8 Thrombin Inhibitor Examples Torsten Steinmetzer 5.9 HIV-1 Protease Drug Development Examples Paul J Ala and Chong-Hwan Chang 5.10 Metalloproteinase–Collagenase Inhibitor Examples Claudiu T Supuran and. .. enthalpy change HDBC hormone-dependent breast cancer HIV human immunodeficiency virus 17bHSD 17bhydroxysteroid dehydrogenase HSP90 heat shock protein I inhibitor IEF isoelectric focusing IR infrared KNF Koshland–Nemethy–Filmer Model LBHB low barrier hydrogen bond LHRH luteinizing hormone-releasing hormone MAO monoamine oxidase MCF-7 human breast cancer cells MMPs matrix metalloproteinases MMPIs MMP inhibitors... Thrombin Inhibitor Examples Torsten Steinmetzer 5.9 HIV-1 Protease Drug Development Examples Paul J Ala and Chong-Hwan Chang 5.10 Metalloproteinase–Collagenase Inhibitor Examples Claudiu T Supuran and Andrea Scozzafava © 2005 by CRC Press . Anhydrase: Its Inhibitors and Activators Edited by Claudiu T. Supuran, Andrea Scozzafava and Janet Conway Enzymes and Their Inhibitors: Drug Development Edited by H. John Smith and Claire Simons ©. Inhibitors Series Enzymes and Their Inhibition Drug Development Edited by H. John Smith and Claire Simons © 2005 by CRC Press This book contains information obtained from authentic and highly regarded. Cataloging-in-Publication Data Enzymes and their inhibition: drug development / edited by H. John Smith and Claire Simons. p.; cm. — (Enzyme inhibitor) Includes bibliographical references and index. ISBN 0-415-33402-0