Enzymes and Their Inhibition

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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 (alk. paper) 1. Enzyme inhibitors. 2. Drug development.

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Enzymes and Their Inhibition Drug Development © 2005 by CRC Press
CRC Enzyme Inhibitors Series Series Editors H. John Smith and Claire Simons Cardiff Univeristy Cardiff, UK 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
CRC Enzyme Inhibitors Series Enzymes and Their Inhibition Drug Development Edited by H. John Smith and Claire Simons CRC PR E S S Boca Raton London New York Washington, D.C. © 2005 by CRC Press
Library of Congress 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 (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 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. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microﬁlming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. All rights reserved. Authorization to photocopy items for internal or personal use, or the personal or internal use of speciﬁc clients, may be granted by CRC Press, provided that $1.50 per page photocopied is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. The fee code for users of the Transactional Reporting Service is ISBN 0-415-33402-0/05/$0.00+$1.50. The fee is subject to change without notice. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. The consent of CRC Press does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Speciﬁc permission must be obtained in writing from CRC Press for such copying. Direct all inquiries to CRC Press, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identiﬁcation and explanation, without intent to infringe. Visit the CRC Press Web site at www.crcpress.com © 2005 by CRC Press No claim to original U.S. Government works International Standard Book Number 0-415-33402-0 Library of Congress Card Number 2004055375 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper © 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 © 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. © 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. © 2005 by CRC Press
Contributors Paul J. Ala Neil R. Kitteringham Incyte Corporation Department of Pharmacology and Wilmington, Delaware Therapeutics University of Liverpool Anthony J. Berdis Liverpool, United Kingdom Department of Pharmacology Case Western Reserve University Irene Lee Cleveland, Ohio Department of Chemistry Case Western Reserve University Cleveland, Ohio Angela Casini Department of Chemistry W. Edward Lindup University of Florence Department of Pharmacology and Florence, Italy Therapeutics University of Liverpool Chong-Hwan Chang Liverpool, United Kingdom Bristol-Myers Squibb Company Princeton, New Jersey Edward A. Meighen Department of Biochemistry Hans-Ulrich Demuth McGill University Probiodrug Research Ltd Montreal, Quebec, Canada Weinbergweg Research Ltd Halle, Germany André J. Neistroj Probiodrug Research Ltd Weinbergweg Research Ltd Samer Haidar Halle, Germany Faculty of Pharmaceutical and Medicinal Chemistry Bruce A. Palfey University of the Saar Department of Biological Chemistry Saarbrucken, Germany University of Michigan Medical School Ann Arbor, Michigan Rolf W. Hartmann Faculty of Pharmaceutical and Andrea Scozzafava Medicinal Chemistry Department of Chemistry University of the Saar University of Florence Saarbrucken, Germany Florence, Italy © 2005 by CRC Press
Claire Simons Jure Stojan Welsh School of Pharmacy Institute of Biochemistry Cardiff University University of Ljubljana Cardiff, United Kingdom Ljubljana, Slovenia Claudiu T. Supuran H. John Smith Department of Chemistry Welsh School of Pharmacy University of Florence Cardiff University Florence, Italy Cardiff, United Kingdom L.W. Lawrence Woo Department of Pharmacy and Torsten Steinmetzer Pharmacology Curacyte Chemistry GmbH University of Bath Jena, Germany Bath, United Kingdom © 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 17a-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 DG free energy change GABA a-aminobutyric acid © 2005 by CRC Press
GABA-T GABA transaminase GnRH gonadotrophin-releasing hormone DH 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 MT-MMP membrane-type MMP MWC Monod–Wyman–Changeux Model NADP nicotinamide adenine dinucleotide phosphate NMR nuclear magnetic resonance NSAI nonsteroidal aromatase inhibitor Ntn N-terminal nucleophile OATP 1 organic anion transporter-1 OC oral contraceptive ODC ornithine decarboxylase P450arom aromatase PAGE polyacrylamide gel electrophoresis PARP poly(ADP-ribose)polymerase PARs protease activatable receptors PC prostate cancer PDB protein data base PEG polyethylene glycol Pi inorganic phosphate PR HIV protease PXR pregnane X receptor QSAR quantitative structure–activity relationship a 5a-R 5a-reductase RT reverse transcriptase DS entropy change S substrate SAM S-adenosylmethionine SAR structure–activity relationship SDS-PAGE sodium dodecylsulfate polyacrylamide gel electrophoresis STS steroid sulfatase T testosterone TPP thiamine pyrophosphate © 2005 by CRC Press
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 Jure Stojan Chapter 5 Development of Enzyme Inhibitors as Drugs H. John Smith 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 Andrea Scozzafava © 2005 by CRC Press