Successful Drug Discovery, Volume 2

János Fischer, Wayne E. Childers, János Fischer, Wayne E. Childers

• Publisher: Wiley-VCH
• Year: 2016
• Print ISBN:
  9783527341153
• eBook ISBN:
  9783527800346
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Retaining the successful approach found in the previous volume in this series, the inventors and primary developers of drugs that successfully made it to market tell the story of the drug's discovery and development and relate the often twisted route from the first candidate molecule to the final marketed drug.
11 selected case studies describe recently introduced drugs that have not been previously covered in textbooks or general references. These range across six different therapeutic fields and provide a representative cross-section of the current drug development efforts. Backed by copious data and chemical information, the insight and experience of the contributors makes this one of the most useful training manuals that a junior medicinal chemist can hope to find and has won the support and endorsement of IUPAC.

Part I
HDAC Inhibitor Anticancer Drug Discovery

Chapter 1
From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design

Ronald Breslow

1.1 Introduction

This is an account of aspects of a collaboration between Ronald Breslow (originally Professor of Chemistry at Columbia University, also a member of the Biological Sciences Department, now University Professor at Columbia) and Paul Marks (originally Professor of Human Genetics and Medicine, Dean of the Faculty of Medicine, then Vice President for Health Sciences and Director of the Comprehensive Cancer Center at Columbia University, then President and Chief Executive Officer at Memorial Sloan Kettering Cancer Center, now President Emeritus and Member of the Sloan Kettering Institute) in the invention and development of suberoylanilide hydroxamic acid (SAHA), an effective anticancer agent that has been in human use for years after approval in the United States, Canada and more recently Japan. The Breslow group designed new potential molecules and carried out their syntheses in the Columbia University chemistry department, and submitted them to Paul Marks and Richard Rifkind at the Columbia Cancer Center, and later at the Sloan Kettering Institute for Cancer Research, for biological evaluation. Paul Marks instituted the collaboration, based on some work by Charlotte Friend of Mount Sinai School of Medicine.

This is the way most modern pharmaceuticals are created in pharmaceutical companies or in academic medicinal departments. Biologists may be aware of a promising area for drug development, medicinal chemists then design and create candidate molecules and send them to the biologists, who then evaluate them. With promising results, the chemists continue to create new, perhaps better, candidates while the biologists extend testing to animals and then to humans. Successful medicines are then approved for human use.

Normally the chemists are aware of compounds that have some promise, based on binding studies, and they can design around those structures. In the case of SAHA, the initial lead, dimethylsulfoxide (DMSO) 1, was very far from a potential medicine so the design was based on a series of hypotheses. Even so, the eventual structure of SAHA proved to be ideal as a binder to the biological target, although this is not how it was discovered. Thus the editors of this volume have invited me to describe the unusual intellectual history that led to its structure. I am a physical organic chemist who had designed and created new molecules for novel properties, such as unusual conjugative stability or instability, or effective catalytic enzyme mimics, but not medicinal properties. However, I have a Master’s degree in Medical Science from Harvard University in addition to my Ph.D. in Chemistry, and I had been a consultant with pharmaceutical companies for many years. There I proposed both new synthetic approaches to their target compounds and also possible alternative medicinal targets themselves.

A few years ago, Paul Marks and I wrote a short review describing the work of both our labs in the development of SAHA [1], but the present chapter will concentrate only on the chemical approach that led to drug development. Thus it does not describe in detail the brilliant biological work done by Paul Marks and Richard Rifkind. The references are only those in which Paul Marks and I are both authors, and it will not cover the many papers and a book produced by the Marks lab alone and several papers from only our lab that related the SAHA story to our other work.

1.2 The Discovery of SAHA (vorinostat)

Stem cells have two functions. They multiply to form additional stem cells, and they differentiate to adult tissue cells with specialised functions. In 1966 Paul Marks approached me with the information that Charlotte Friend had seen something remarkable [2, 3]. When a suspension of murine erythroleukemia cells (MELC) was treated with dimethylsulfoxide (DMSO) (1) at 280 mmol...

Table of contents

• Cover
• Table of Contents
• Title
• Copyright
• Preface
• List of Contributors
• Part I: HDAC Inhibitor Anticancer Drug Discovery
• Part II: Steroidal CYP17 Inhibitor Anticancer Drug Discovery
• Part IV: Central Nervous System (CNS) Drug Discovery
• Part V: Antiulcer Drug Discovery
• Part VI: Cross-Therapeutic Drug Discovery (Respiratory Diseases/Anticancer)
• Index
• End User License Agreement