Privileged Structures in Drug Discovery

Medicinal Chemistry and Synthesis

Larry Yet

• Publisher: Wiley
• Year: 2018
• Print ISBN:
  9781118145661
• eBook ISBN:
  9781118686331
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

A comprehensive guide to privileged structures and their application in the discovery of new drugs 

The use of privileged structures is a viable strategy in the discovery of new medicines at the lead optimization stages of the drug discovery process.  Privileged Structures in Drug Discovery offers a comprehensive text that reviews privileged structures from the point of view of medicinal chemistry and contains the synthetic routes to these structures. In this text, the author—a noted expert in the field—includes an historical perspective on the topic, presents a practical compendium to privileged structures, and offers an informed perspective on the future direction for the field.

The book describes the up-to-date and state-of-the-art methods of organic synthesis that describe the use of privileged structures that are of most interest. Chapters included information on benzodiazepines, 1,4-dihydropyridines, biaryls, 4-(hetero)arylpiperidines, spiropiperidines, 2-aminopyrimidines, 2-aminothiazoles, 2-(hetero)arylindoles, tetrahydroisoquinolines,  2,2-dimethylbenzopyrans, hydroxamates, and bicyclic pyridines containing ring-junction nitrogen as privileged scaffolds in medicinal chemistry. Numerous, illustrative case studies document the current use of the privileged structures in the discovery of drugs. This important volume:

• Describes the drug compounds that have successfully made it to the marketplace and the chemistry associated with them
• Offers the experience from an author who has worked in many therapeutic areas of medicinal chemistry
• Details many of the recent developments in organic chemistry that prepare target molecules
• Includes a wealth of medicinal chemistry case studies that clearly illustrate the use of privileged structures

Designed for use by industrial medicinal chemists and process chemists, academic organic and medicinal chemists, as well as chemistry students and faculty, Privileged Structures in Drug Discovery offers a current guide to organic synthesis methods to access the privileged structures of interest, and contains medicinal chemistry case studies that document their application.

1
Introduction

1.1 The Original Definition of Privileged Structures

In 1988, Ben Evans and his research team at Merck in their quest for potent, selective, orally effective cholecystokinin (CCK) antagonists studied the prototype 3‐(acylamino)‐5‐phenyl‐2H‐1,4‐benzodiazepines as therapeutic agents derived from the natural product lead asperlicin [1]. Evans recognized the core structure exhibited affinity toward central and peripheral benzodiazepine, opiate, CCK‐A, α‐adrenergic, serotonin, muscarinic, and angiotensin I receptors. To quote verbatim from the words of Ben Evans in this seminal publication, which set in force the term “privileged structures” for the next three decades in two different paragraphs:

Thus, this single ring system, the 5‐phenyl‐1,4‐benzodiazepine ring, provided ligands for a surprisingly diverse collection of receptors, the natural ligands for which appear to bear little resemblance to one another or to the benzodiazepines in question. The only obvious similarity is among the benzodiazepine structures themselves. These structures appear to contain common features which facilitate binding to various proteinaceous receptor surfaces, perhaps through binding elements different from those employed for binding of the natural ligands.

Arguments have been constructed to suggest that structures with high affinity for a given receptor may be more numerous, but at the same time more difficult to pinpoint than has heretofore been appreciated. The development of the compounds described here has illustrated an approach to that end having potentially wider utility, selective modification of “privileged structures” known to have provided ligands for diverse receptors in the past.

IUPAC has provided a structural definition of privileged structures—“Substructural feature which confers desirable (often drug‐like) properties on compounds containing that feature. Often consists of a semi‐rigid scaffold which is able to present multiple hydrophobic residues without undergoing hydr...

Table of contents

• Cover
• Title Page
• Table of Contents
• 1 Introduction
• 2 Benzodiazepines
• 3 1,4‐Dihydropyridines
• 4 Biaryls
• 5 4‐(Hetero)Arylpiperidines
• 6 Spiropiperidines
• 7 2‐Aminopyrimidines
• 8 2‐Aminothiazoles
• 9 2‐(Hetero)Arylindoles
• 10 Tetrahydroisoquinolines
• 11 2,2‐Dimethylbenzopyrans
• 12 Hydroxamates
• 13 Bicyclic Pyridines Containing Ring‐Junction Nitrogen
• Index
• End User License Agreement