Peptidomimetics Protocols / Edition 1

by Wieslaw M. Kazmierski

Overview

Many physiologically important receptors and enzymes are regulated by their endogenous ligands and inhibitors. Nature chose to utilize these p- tides as chemical switches since they can be efficiently synthesized and - graded in cells, thus providing an immediate response to a fast changing environment. Such properties, so critical in cell survival, make peptides less than ideal drug candidates. Other frequently desired properties in drug m- ecules include oral bioavailability, the ability to cross membranes, including the blood-brain barrier, and sufficient stability for administration 1-2 times a day. In spite of these obstacles, some natural peptides and proteins are ind- putably successful medicines and have become drugs of choice. Further - vances in peptide-based pharmaceuticals are critically dependent on both new delivery methods and new chemical approaches to the conversion of these molecules to druglike entities. In addition, peptides are also the natural sta- ing points for optimization of their pharamacological and chemical prop- ties, which may lead to superior drugs. Peptidomimetics Prools deals with both aspects of peptide pharmaceuticals, through the tools of modern s- thetic and medicinal chemistry. The last decade has witnessed a steady stream of new synthetic approaches to peptide mimetics, compounds that replace phy- ologically vulnerable peptide functionalities with chemical modules of - creased stability and cellular penetration. The chapters have been written by both academic and industrial chemists, and focus on the practical synthetic preparation of peptide mimetics.

Product Details

ISBN-13:	9780896035171
Publisher:	Springer-Verlag New York, LLC
Publication date:	10/19/1998
Series:	Methods in Molecular Medicine , #23
Edition description:	1999
Pages:	549
Product dimensions:	6.10(w) x 9.25(h) x 0.06(d)

About the Author

Kazmierski, Wieslaw M. (Glaxo Wellcome Research)

Table of Contents

Synthesis and Use of Pseudopeptides Derived from 1,2,4-Oxadiazole-, 1,3,4-Oxadiazole-, and 1,2,4-Triazole-based Dipeptidomimetics.- Synthesis of Aminobenzoic Acid-Based Nonpeptide Templates: Applications in Peptidomimetic Drug Discovery.- Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model Hexapeptide Having Enhanced Membrane Permeability and Enzymatic Stability Using an Acyloxyalkoxy Promoiety.- Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model Hexapeptide Having Enhanced Membrane Permeability and Enzymatic Stability Using a 3-(2?-Hydroxy-4?,6?-Dimethylphenyl)-3,3-Dimethyl Propionic Acid Promoiety.- Synthesis of Coumarin-Based, Esterase-Sensitive Cyclic Prodrugs of Opioid Peptides with Enhanced Membrane Permeability and Enzymatic Stability.- Azatides as Peptidomimetics: Solution and Liquid Phase Syntheses.- Synthesis of Cbz-Protected Ketomethylene Dipeptide Isosteres.- (E)-Alkene Peptide Bond Isosteres by Cuprate Opening of Vinyl Aziridines.- Syntheses of Norstatine, Its Analogs, and Dipeptide Isosteres by Means of—-Lactam Synthon Method.- Synthesis of a Versatile Peptidomimetic Scaffold.- An Asymmetric Synthesis Prool to Prepare Topographically Constrained—-Substituted Aromatic Amino Acids.- Synthesis of Oligopeptides Containing an Oxirane Ring in the Place of a Peptidic Bond.- Synthesis of Protected Lactam-Bridged Dipeptides.- Synthesis of Peptidomimics Through Sugar-Based Scaffolds.- The Synthesis of Bicyclic Piperazinone and Related Derivatives.- Synthesis of Dipeptides with—[CH20] Amide Bond Mimetics.- SNAr-Based Cycloetherification Methodology: Application in the Synthesis of Heterodectic Macrocyclic Peptides with Endo Aryl-Aryl and Aryl-Alkyl Ether Bonds.- Cyclic Aromatic Amino Acids with Constrained—1 and—2 DihedralAngles.- Asymmetric Syntheses of Unnatural Amino Acids and Hydroxyethylene Peptide Isosteres.- Fluoroolefin Isosteres.- Synthesis of 3-Amino-l-CarboxymethyI-Benzodiazepine (BZA) Peptidomimetics.- A Conformationally Restricted—-Strand HIV Protease Inhibitor.- Synthesis of Cyclopropane-Containing Leu-Enkephalin Analogs.- The 1,5-Disubstituted Tetrazole Ring as a cis-Amide Bond Surrogate.- Synthesis of (2R, 3R, 4R, 5S)-5-tert-Butyloxycarbonylamino-3,4-Dihydroxy-2-1sopropyl-3,4-O,O-Isopropylidene-6-CyctohexyI-Hexanoic Acid.- Synthesis of (2S, 4S, 5S)-5-(t-Butoxycarbonylamino)-4-(t-Butyldimethylsilyloxy)-2-Isopropyl-7-Methyl Octanoic Acid.- Synthesis of—-Vinyl Amino Acids.- A Novel Synthetic Prool for the Preparation of Enantiopure 3-, 4-, and 5-Substituted Prolines.- Synthesis of Aminobenzoic Acid-Based Nonpeptide Templates.- Aminimides as Peptidomimetics.

Editorial Reviews

"The editor has assembled an interesting collection of synthetic methods for preparing peptidomimetics. . .This book will clearly be of value to those who are interested in synthesizing nonpeptidic analogues of small peptide ligands."-Journal of Medicinal Chemistry

"the editor does an excellent job of bringing together a variety of different chemical syntheses that are relevant to peptide, peptidomimetic, combinatorial and medicinal chemistry. Each chapter is written in the same general format of introduction, materials, methods, notes and references, which is always valuable for a book that will be regularly consulted. In addition, many of these are reported by acknowledged leaders in the field. . . includes a number of novel amino acid syntheses that will be extremely

valuable to those scientists trying to understand the underlying medicinal chemistry of peptides. . . the contents of this book are extremely valuable and I have no doubt it will find its way into many of the world's leading industrial and academic organic chemistry laboratories."-Drug Discovery Today

From the Publisher

A collection of detailed procedures for synthesizing a variety of scaffolds, turn mimetics, peptide-bound replacements, and enzyme inhibitors. The 30 contributions discuss unusual syntheses of amino acids, the use of linear and heterocyclic scaffolds in place of the peptide backbone, and synthetic protocols for transition-state mimics and reactive "warheads" applicable in enzyme inhibitors. Significant chemical procedures and methods include the transient protection of charged peptides as neutral prodrugs for improved blood-brain penetration, and the replacement of peptide bonds with heterocyclic rings, olefins and fluoroolefins, and ketomethylenes. Annotation c. by Book News, Inc., Portland, Or.

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