Progress in Medicinal Chemistry 3 5

Progress in MedUicinal Chemistry 35 This Page intentionally left blank Progress in Medicinal Chemistry 3 5 Editors: G.P. ELLIS,D.SC., PH.D., F.R.S.C. Department of Chemistry University of Wales P.0. Box 912, Card18 CFI 3 TB United Kitigdom D.K. LUSCOMBE, B.PHARM., PH.D., F.I.BIOL., F.R.PHARM.S Welsh School of Pharmacy University of Wales P.0. Box 13, Cardig CFI 3XF United Kingdom and A.W. OXFORD, M.A., D.PHIL. Consultant in Medicinal Cheniistry P. 0. Box 151 Royston SG8 5 YQ United Kingdom 1998 ELSEVIER AMSTERDAM LAUSANNE- NEW YORK *OXFORD*SHANNON*SINCAPORE -TOKYO Elsevier Science BV P.O. Box 21 1 1000 AE Amsterdam The Netherlands Library of Congress Cataloging in Publication Data: Please refer to card number 62-2712 for this series. ISBN 0-444-82909-1 ISBN Series 0-7204-7400-0 0 1998 Elsevier Science BV. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the Publisher, Elsevier Science B.V., Copyright and Permissions Department, P.O. Box 521, 1000 AM Amsterdam, The Netherlands. No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, the Publisher recommends that independent verification of diagnoses and drug dosages should be made. Special regulations for readers in the USA: This publication has been registered with the Copyright Clearance Center Inc. (CCC), Salem, Massachusetts. Information can be obtained from the CCC about conditions under which the photocopying of parts of this publication may be made in the USA. A11 other copyright questions, including photocopying outside of the USA, should be referred to the Publisher. @ The paper used in this publication meets the requirements of ANSIiNISO 239.48-1992 (Permanence of Paper). Printed in The Netherlands V Preface Five topics are reviewed in this volume. Chapter 1 traces the biochemical and medical significance of Vitamin D and its derivatives from the first quar- ter of this century, a field which continues to promise further valuable results. In contrast, the relatively recent development of neurokinin antagonists, especially NKI-selective compounds, is surveyed in Chapter 2. These compounds have potential for the treatment of pain, migraine, emesis and asth- ma. A plethora of types of compound structures have recently been found to possess selective antagonism for each of the neurokinin receptors. Chapter 3 surveys recent progress in our understanding of opioid antagonists and of their therapeutic potentials. Bacterial resistance to antibacterial agents and especially chemotherapeutic drugs is of increasing importance. Current knowledge of the mechanisms involved in resistance together with ways of combating this threat to successful chemotherapy is discussed in Chapter 4. Much progress has recently been made in our understanding of structure- activity relationships of cannabinoids. In view of the current interest in the clinical usefulness of these compounds as analgesics, Chapter 5 gives a timely survey of present scientific knowledge of these drugs. We are grateful to our authors for condensing the vast literature of these topics and to owners of copyright material for permission to reproduce, and to our publishers for their encouragement. September 1997 G. P. Ellis D. K. Luscombe A. W. Oxford This Page intentionally left blank vii Contents Preface 1. Modern View of Vitamin D3 and its Medicinal Uses Matthew J. Beckman, Ph.D. and Hector F. DeLuca, Ph.D. Department of Biochemistry, College ofAgricultura1and Life Sciences, University of Wisconsin-Madison, 420 Henry Mall, Madison, Wisconsin 53 706 2. Neurokinin Receptor Antagonists 57 Christopher J. Swain, Ph.D. Merck, Sharp and Dohme Research Laboratories, Neuroscience Reseurch Centre, Terlings Park, Hurlow, Essex. CM20 2QR, U.K. 3. Opioid Receptor Antagonists 83 Helmut Schmidhammer, Ph.D. Institute of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52a, A-4020 Innsbruck, Austria 4. Mechanisms of Bacterial Resistance to Antibiotics and 133 Biocides A.D. Russell, D.Sc. Welsh School of Pharnzacy, University of Wales, Curdig CFl3XE UK 5 Towards Cannabinoid Drugs - Revisited 199 R. Mechoulam, Ph.D., L. HanuS, Ph.D. and Ester Fride, Ph.D. Brettler Medicul Reseurch Center, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerern, Jerusulem 91 120, Israel Subject Index 245 Author Index (Vols. 1-35) 25 1 Subject Index (Vols. 1-35) 255 This Page intentionally left blank Progress in Medicinal Chemistry - Vol. 35 Edited by G.P. Ellis, D.K. Luscombe and A.W. Oxford 0 1998 Elsevier Science B.V. All rights reserved. 1 Modernview of Vitamin D3 and its Medicinal Uses MATTHEW J. BECKMAN. PH.D. AND HECTOR F. DELUCA, PH.D. Department of Biochemistry, College of Agricultural und Lfe Sciences, University of Wisconsin-Madison, 420 Henry Mall, Madison, Wisconsin 53706 INTRODUCTION 2 METABOLISM OF VITAMIN D3 5 Biosynthesis ofvitamin D3 in skin 5 Functional metdbohn of vitamin D1 8 REGULATION OF VITAMIN D? METABOLISM 12 Hepatic vitamin D3-25-hydroxylase 12 Renal 24- and 1 r-hydroxylases: Reciprocal regulation 14 Other factors regulating Irx-OHase 17 Biological effects of 1,25-(OH)zD3 19 Extrarenal metabolism of 1,25-dihydroxyvitamin Dq 21 MOLECULAR MECHANISM OF I .25-DIHYDROXYVITAMIN Dq ACTION 24 The 1,25-(OH)2Dq-receptor(VDR) 24 Structure and function of VDR 25 Mo~eculdrbiology of VDR function 1,25-(OH)2D3 (response elements) 27 Regulation of 1,25-(OH)zD~responsive genes 29 VDR uplahe 29 Plrocpliori kt~ton 30 Moletulur nioddoj 1,25-(OH/~D~-tlependt~ntgcne tranrcrtption 31 TREATMENT OF CALCIUM AND PHOSPHORUS DISORDERS WITH VITAMIN D3 METABOLITES AND ANALOGUES 34 Renal osteodystrophy 34 Fanconi syndrome 34 X-linked hypophosphataemia vitamin D-resistant rickets 35 Vitamin D-dependency rickets type I 35 Vitamin D-dependency rickets type I1 36 Osteoporosis 36 2 MODERN VIEW OF VITAMIN D3 AND ITS MEDICINAL USES VITAMIN D3 ANALOGUES OF CLINICAL IMPORTANCE FOR OTHER TYPES OF DISEASES 38 Psoriasis 38 Immunobiology 39 Differentiation 40 CONCLUDING REMARKS 42 ACKNOWLEDGEMENTS 43 REFERENCES 43 INTRODUCTION The involvement of vitamin D as an accessory food substance in the health of individuals has been well-known since the turn of the century stemming mainly from studies investigating the cause of rickets. The disease rickets is characterized by the failure of mineralization of the bone matrix and/or growth plate and is marked by dramatic skeletal deformities. The documen- tation of this disease extends back to ancient times, but the sharp rise in the incidence of rickets and osteomalacia (the adult form of rickets) in the Uni- ted States and Northern Europe at the approximate time of the Industrial Revolution stimulated a surge of determined interest in clarifying the aetiol- ogy of rickets [ 13. The three most profound determinants contributing to the cause of rickets were undernourishment, pollution and the implementa- tion of long workdays in factories especially by young growing children. Perhaps the most significant of the early classical studies was that of Sir Edward Mellanby in 1919 experimenting with dogs. He induced rickets by housing them indoors and feeding them oatmeal [2]. Around this time, McCollum and his co-workers had discovered a potent substance in cod liver oil that he termed vitamin A which was active in preventing diseases of deficiency such as xeropthalmia and night blindness [3]. Mellanby demonstrated that cod liver oil was also effective in curing rickets in dogs, but he considered that vitamin A was the important nutritional factor responsible for healing rickets. McCollum et al. destroyed vitamin A in cod liver oil by heating and oxidation, but found that the antirachitic factor remained [4]. The antirachitic factor was given the name vitamin D by McCollum. In ad- dition, other observations provided the rationale indicating that UV irradiation is beneficial in the healing of rickets. Steenbock and Black tied both the nutritional and environmental observations together by demonstrating the formation of the antirachitic factor in skin and the fat-soluble fraction of M.J. BECKMAN AND H.F. DELUCA 3 foods by UV irradiation [5]. Hess and Weinstock confirmed Steenbock and Black’s results and this led eventually to the isolation and identification of ergocalciferol (vitamin D2)from plants [6]. At first, vitamin D2 was thought to be the same antirachitic factor of fish oils until it was found to be less active in curing rickets in chickens [7, 81. In 1936, Windaus et al. synthesized 7-dehydrocholesterol and demonstrated its conversion via UV irradiation to cholecalciferol (vitamin D3), the natural form of vitamin D in animal spe- cies [9]. Vitamin D3 differs from vitamin D2 by not having a c-24 methyl group and a double bond at C-22. From the discovery of Steenbock and Black, effective methods were developed to introduce vitamin D into foods, eliminating rickets as a major medical problem in developed countries throughout the northern hemisphere. The relationship of serum calcium and phosphate with rickets was discovered by Howland and Kramer [lo]. They found that blood from normal rats could mineralize rachitic rat cartilage, whereas blood from rachitic rats could not. They also provided evidence that a low serum calcium and phosphate status caused rickets. Orr rt al. [l 11 demonstrated that UV irradiation stimulated calcium absorption. This study was largely unappreciated for 30 years until Nicolaysen and Eeg-Larsen [12] and Schachter and Rosen [13] demonstrated evidence for vitamin D-induced intestinal absorption of calcium by an active transport process.

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