Peptide-Based Drug Design: Controlling Transport and Metabolism

Peptide-Based Drug Design: Controlling Transport and Metabolism Editors: Michael D. Taylor and Gordon L. Amidon. American Chemical Society, Washington...
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J. Med. Chem. 1996, 39, 1189-1191

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Book Reviews Peptide-Based Drug Design: Controlling Transport and Metabolism. Editors: Michael D. Taylor and Gordon L. Amidon. American Chemical Society, Washington, D.C. 1995. xviii + 567 pp. 18.5 × 26 cm. ISBN 0-8412-3058-7. $99.95. This book contains 22 chapters reviewing peptide transport and metabolism. It developed from a 1992 symposium on prodrugs of peptidomimetics. This theme expanded to cover a range of topics about the transport and metabolism of peptide-based drugs. Chapters 1-4 provide a general introduction of amino acid/peptide transport, peptide metabolism in various tissues, and the pharmaceutical properties and pharmacokinetics of peptide drugs. The focus of chapters 5-9 is intestinal peptide transport mechanisms. Our understanding of intestinal peptide transport and example studies are described in detail. This illustrates the various aspects needed to design transport properties into peptide-based drugs. In chapters 10 and 11 the authors discuss liver processing of peptides and how to modulate their transport into the liver. The mechanisms for liver processing of peptides are complex and not well understood. The authors clearly define what is known about these mechanisms and show the need to address this processing in peptide drug development. Blood-brain barrier peptide transport is covered in chapters 12-14. Peptides do not freely cross this barrier due to their hydrophilic character. Several strategies for enhancing peptide drug delivery to the central nervous system are reviewed. In chapters 15 and 16 peptide transport in bacteria and fungi is reviewed. Understanding these phenomena not only will be useful for designing improved antimicrobials but may also serve as useful models for general peptide transport. How to improve the duration of action of peptide drugs is addressed in chapters 17-19. Limiting metabolism with peptidomimetics and prodrugs is discussed in the first two chapters. In chapter 19 the author describes the drug depot concept as a way of increasing the duration of action. The last section of this book concerns experimental systems used to evaluate peptide transport and metabolism. This will be very useful to the reader contemplating strategies for developing a peptide-based drug since the drug design process is an incremental one requiring evaluation at each step. Overall, this book is timely, and most discussions are presented clearly. It should prove to be a useful resource for scientists involved in the discovery and development of peptide-based drugs. Richard S. Pottorf Hoescht Marion Roussel, Inc. 2110 E. Galbraith Road Cincinnati, Ohio 45215 JM950847J

Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. C. Hansch, A. Leo, and D. Hoekman. American Chemical Society, Washington, DC. 1995. Xix + 348 pp. 22 × 28.5 cm. Exploring QSAR: Fundamentals and Applications in Chemistry and Biology. C. Hansch and A. Leo. American Chemical Society, Washington, DC. 1995. Xvii + 557 pp. 18.5 × 26 cm. ISBN 0-8412-2993-7 (set). $99.95 (set). This pair of books is a welcome addition to the literature of computer-assisted molecular design. Together they represent a summary of the three decades of intense work by Corwin Hansch and his many collaborators on the relationships between the physical and biological properties of molecules. The thousands of equations in this book document the insights that can be gained by considering the statistical relationship between the hydrophobic, steric, and electronic effects of substituents on the biological activity of molecules. The volume of substituent constants is a long-awaited update of Hansch and Leo’s earlier compilation. It contains 16 777 measured octanol-water log P values with the associated references to the original literature and 115 pages of electronic and steric constants with 1016 references. The log P values of the highest quality are indicated. These log P’s and substituent constants will be invaluable for those who wish to derive their own QSAR equations or merely to think about physical properties of compounds of interest. The companion volume on fundamentals and applications of QSAR consists of 13 chapters. The first 168 pages of the book present a general discussion of the physical organic chemistry behind QSAR. It includes chapters on electronic effects of substituents on organic reactions, examples of applications of the Hammett equation, a discussion of steric effects, a discussion of hydrophobicity, and a detailed chapter on the methods for calculation of log P. Each of these chapters contains many specific applications as well as explanations of how to interpret the relationships. The second part of the book provides detailed expositions of QSAR as related to different biological endpoints. Each chapter contains many QSAR equations based mainly on the traditional parameters. Chapters discuss the QSAR of nonspecific toxicity; of proteins and enzymes; in metabolism; of mutagenesis, carcinogenesis, and antitumor drugs; of CNS agents, of anti-infective agents; and of pesticides. The final chapter is a general one on aspects of the design of bioactive compounds. It includes a table for 230 well-characterized substituents of aromatic rings with values for hydrophobic π; field (F) and resonance

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Book Reviews

(R) electronic effects; and MR, a measure of size. It is arranged according to distance from hydrogen to aid the design of a varied series. Every chapter of the book is impressive in the wealth of detailed information provided, usually in the form of regression equations. For example the chapter on applications of the Hammett equation has 174 equations. Early QSAR results are presented and many have been re-derived to bring them up to current standards. The equations for similar biological endpoints are compared and contrasted with each other to put each in context with each other and with known biochemistry of the system. The information is put into historical context with extensive referencing starting with Ehrlich, Meyer, and Overton. These books should be studied by anyone practicing computer-assisted molecular design or interested in what can be gained by a QSAR analysis. In view of the recent emphasis on structure-based drug design, the chapter on proteins and enzymes is especially informative in that frequently the structure-activity relationships show electronic effects of substituents on a position remote from the substituent. Such effects would be difficult to discern from molecular graphics analysis and would probably be a challenge for molecular dynamics. It is only by considering hydrophobic, steric, and electronic effects on biological activity that one can understand the basis of structure-activity relationships.

isoquinolines occur in this volume. However, the section devoted to natural products specifically only occupies a page or less, no doubt frustrating natural product chemists. The contributors faced a task of significant magnitude covering a wide time span of literature (references begin in the 1920s and extend to 1990). Generally, they succeeded admirably; insight and mechanistic interpretation are frequently included. However, there are a few sections which seem to be little more than abstract services and compressed ones at that. Delays in manuscript preparation have resulted in a literature gap in book publication in the range of 5-9 years. A curious compound numbering approach was used in the section on hydroxy and thiol derivatives. Numbers appear haphazardly, making the text and diagrams difficult to coordinate. The tables of contents are concise but clearly explanatory; the seven-page index is adequate; however no author index is included. Editorial quality is highsfew typographical errors appear although some structural diagrams are more “crisp” than others. The price of this volume likely dictates that it will be found largely in libraries where it doubtless has already attracted many readers.

Yvonne Connolly Martin Pharmaceutical Products Division Abbott Laboratories Abbott Park, Illinois 60064-3500 JM950902O

Heterocyclic Compounds. Isoquinolines. Volume 38. Part 3. Edited by Gary M. Coppola and Herbert F. Schuster. John Wiley & Sons, Inc., New York. 1995. xi + 552 pp. 16 × 24 cm. ISBN 0-471-62853-7. $225.00. These handsome dark red/dark blue volumes are one of the mainstays of the literature of heterocyclic chemistry. The nearly all-inclusive scope of the series and high quality make them one of the first sources a heterocyclic chemist chooses to gain perspective on the myriad faces of this field. A well-qualified and prestigious group of contributors from both industry and academia and from far-flung sites has cooperated to produce this volume, a valuable and still pertinent compilation of the chemistry of derivatives of isoquinolinessthose bearing basic side chains (Schuster and Kathawala section) and hydroxyl groups or ethercontaining side chains and thiol derivatives (Hoshino, Hara and Umezawa section). The study of the pharmacological or biological activity of these compounds has been the motivation for much of their syntheses and characterization because of the unique activities of many isoquinolines in their own right and because of the presence of an imbedded, conformationally restricted phenethylamine or dopamine moiety in 1,2,3,4-tetrahydro derivatives. Natural product chemistry is also an important aspect of isoquinolines, and over 30 references to natural product

Stephen T. Ross SmithKline Beecham Pharmaceuticals King of Prussia, Pennsylvania 19406-0939 JM9509051

Angiotensin II Receptors Volume 1. Molecular Biology, Biochemistry, and Clinical Perspectives. Edited by Robert R. Ruffolo, Jr. CRC Press, Boca Raton, FL. 1994. 170 pp. 16 × 24 cm. ISBN 0-84938380-3. $99.50; Volume 2. Medicinal Chemistry. 1994. 225 pp. 16 × 24 cm. ISBN 0-8493-8545-3. $99.50. In the last few years our knowledge of the role of angiotensin II and of the receptors through which it operates has advanced rapidly. One important reason for this progress has been the discovery of several series of selective, nonpeptide antagonists of the AII receptors. In addition, the clinical utility of these antagonists has been demonstrated, and the past past few years have seen intensive effort in the pharmaceutical industry to discover and develop AII receptor antagonists. This two-volume set represents a comprehensive but relatively concise review of the biochemistry, pharmacology, and medicinal chemistry of the angiotensin II receptors. The material is timely and extensively referenced, and a subject index is provided. Any medicinal chemist with an interest in this area should find both volumes very readable. The chapter titles and authors of volume 1 are as follows: (1) Introduction: Angiotensin II Receptors by D. P. Brooks and R. R. Ruffolo, Jr.; (2) Angiotensin II Receptor Subclassification by R. M. Edwards and R. R. Ruffolo, Jr.; (3) Molecular Biology of Angiotensin II Receptors by D. J. Bergsma; (4) Angiotensin II Receptor Signal Transduction Mechanisms by R. M. Edwards and R. R. Ruffolo, Jr.; (5) Functions Mediated by Peripheral Angiotensin II Receptors by D. P. Brooks and R. R. Ruffolo, Jr.; (6) Functions Mediated by Angiotensin II

Book Reviews

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Receptors in the Brain by D. P. Brooks and R. R. Ruffolo, Jr.; (7) Therapeutic Applications of Angiotensin II Antagonists by M. I. Freed, B. E. Ilson, N. H. Shusterman, and D. K. Jorkasky. The chapter titles and authors of volume 2 are as follows: (1) Introduction: Medicinal Chemistry of Angiotensin II Receptors by J. G. Gleason and R. R. Ruffolo, Jr.; (2) Structure-Activity Relationships of Peptide Angiotensin II Receptor Agonists and Antagonists by J. Samanen and D. Regoli; (3) Conformational Models of Angiotensin II for Nonpeptide Antagonist Design by J. Samanen, J. Hempel, R. Keenan, C. Peishoff, and J. Weinstock; (4) Structure-Activity Relationships of Nonpeptide Angiotensin II Receptor Antagonists by J. Weinstock and R. M. Keenan.

Electrochemistry for Chemists. Second Edition. By Donald T. Sawyer, Andrzej Sabkowiak, and Julian L. Roberts, Jr. John Wiley & Sons, Inc., New York. 1995. xv + 505 pp. 16.5 × 24 cm. ISBN 0-471-594687. $64.95.

David J. Carini Dupont Merck P.O. Box 80500 Wilmington, Delaware 19880-0500

Pathogenesis and Therapy of Amyotrophic Lateral Sclerosis. Volume 68 (Advances in Neurology). Edited by Georges T. Serratrice and Theodore L. Munsat. Lippincott-Raven, Philadelphia, PA. 1995. xx + 290 pp. 18 × 26 cm. ISBN 0-7817-0333-6. $115.00. JM950848B

Brain Imaging of Nicotine and Tobacco Smoking. Edited by Edward F. Domino. NPP Books, Ann Arbor, MI. 1995. xii + 340 pp. 16 × 23.5 cm. ISBN 0-916182-10-X. $95.00.

JM950901W

Clinical Pulmonary Hypertension (Portland Press Research Monograph). Edited by A.H. Morice. Portland Press Ltd., London. 1995. xi + 280 pp. 15 × 23.5 cm. ISBN 1-85578-074-7. $128.00.

Chemists’ Views of Imaging Centers. Edited by Ali M. Emran. Plenum Publishing Corp., New York. 1995. xiii + 537 pp. 17 × 25.5 cm. ISBN 0-306-449129. $129.50. Protozoan Parasites and Water. Edited by W. B. Betts, D. Casemore, C. Fricker, H. Smith, and J. Watkins. Royal Society of Chemistry, U.K. 1995. x + 260 pp. 16 × 24 cm. ISBN 0-85404-755-7. £49.50. Theoretical and Physical Principles of Organic Reactivity. By Addy Pross. John Wiley & Sons, Inc., New York. 1995. xv + 294 pp. 16 × 24 cm. ISBN 0-471-55599-1. $59.95. Experimental Headache Models. Volume 5 (Frontiers in Headache Research). Edited by Jes Olesen and Michael A. Moskowitz. Lippincott-Raven, Philadephia, PA. 1995. xx + 358 pp. 16 × 24 cm. ISBN 0-7817-0330-1. $89.00.

Nuclear Medicine. Science and Safety. By Alan C. Perkins. John Libbey & Company Ltd., London. 1995. x + 182 pp. 17.5 × 24.5 cm. ISBN 0-86196-4705. $44.00.

Books of Interest

Behavioural Brain Research in Naturalistic and Semi-Naturalistic Settings. Volume 82. Edited by Enrico Alleva, Aldo Fasolo, Hans-Peter Lipp, Lynn Nadel, and Laura Ricceri. Kluwer Academic Publishers Group, Dordrecht, The Netherlands. 1995. xxi + 466 pp. 16.5 × 24.5 cm. ISBN 0-7923-3570-8. $230.00. Medicinal, Essential Oil, Culinary Herb and Pesticidal Plants of the Labiatae. Part 1 19731993. CAB International, Wallingford, U.K. 1994. 227 pp. 21 × 29.5 cm. ISBN 0-85198-954-3. $136.00. JM9508999