Medicinal Chemistry: Fundamentals

By Roland Barret

Medicinal Chemistry: Fundaments presents the cycle of the life of drugs, their physico-chemical properties, and consequences that arise in development. The fundamental concepts of Medicinal Chemistry (pharmacophore, prodrugs, Lipinsky rules) are also presented, including discussions on specific concerns of the European Pharmacopeia – the industrialist’s bible – its role, and a description of the monographs of active principles.

• Defines the lifecycle of drugs
• Explains the physico-chemical properties and consequences of a drug
• Studies the fundamental concepts of medicinal chemistry
• Describes the active ingredient monographs

• Language: English
• Publisher: Elsevier Science
• Release date: Jul 10, 2018
• ISBN: 9780081027608

Roland Barret

Roland Barret is a Professor of Medicinal Chemistry, Laboratory of Therapeutic Chemistry, ISPBL at the University "Claude Bernard Lyon". He began his university studies in October 1968 at the Faculty of Sciences of Lyon where he obtained a master's degree in organic chemistry in 1973 and a diploma of advanced studies in organic chemistry. In 1984, in parallel with his teaching activities at the Faculty of Pharmacy of Lyon and his research activities, he studied pharmacy and obtained the title of pharmacist in 1984 and a second diploma of graduate studies in therapeutic chemistry. He defended my doctoral thesis in Pharmaceutical Sciences in 1987. From 2010 to 2017, he participated in the creation of the University of Science and Technology of Hanoi (Viet Nam) where he taught Therapeutic Chemistry at the Master of Science Pharmaceutics and Technology every year during regular teaching assignments. He is the author of 70 scientific publications on different themes

Book preview

Medicinal Chemistry

Fundamentals

Roland Barret

Series Editor

Max Malacria

Table of Contents

Cover image

Title page

Dedication

Copyright

Preface

1: Medicines and Drugs

Abstract

1.1 Definition of a drug

1.2 A few important dates in the history of drugs

1.3 Different types of drugs

1.4 Classification of drugs

1.5 A few facts about the pharmaceutical industry

1.6 Life cycle of a drug

1.7 Marketing authorization application

1.8 Chemistry, R&D and drug design

2: Importance and Evaluation of the pKa

Abstract

2.1 Definition of the pKa and its implications

2.2 Examples

2.3 Case of zwitterions

2.4 Influence of structure

2.5 Evaluating the pKa

2.6 What is the relevance of the pKa for absorption when a drug is administered orally?

3: Importance and Evaluation of Lipophilicity

Abstract

3.1 Passing through a membrane

3.2 Evaluating lipophilicity

3.3 Use of software

3.4 General points: logD

3.5 Hydrophilic–Lipophilic Balance (HLB): a galenic problem

4: Importance and Evaluation of Solubility

Abstract

4.1 Definitions

4.2 Evaluating solubility on the basis of lipophilicity

4.3 Methods by contribution of groups or fragmentation

4.4 Case of ionizable substrates

4.5 Solubility and druggability

4.6 How to modify solubility

5: Importance and Evaluation of the Polar Surface Area (PSA and TPSA)

Abstract

5.1 Definitions

5.2 Evaluating the polar surface area

5.3 Influences of PSA and TPSA on different physico-chemical properties

5.4 Use of software

6: Lipinski’s Rule of Five

Abstract

6.1 What does Lipinski’s rule say?

6.2 Veber’s rule

7: Principle of a Prodrug

Abstract

7.1 Introduction

7.2 Bioprecursor

7.3 Vector prodrug

8: Pharmacophore

Abstract

8.1 Definition

8.2 3D pharmacophore

8.3 Metabophore and toxicophore

8.4 Modification of the structure

9: The European Pharmacopoeia

Abstract

9.1 Introduction

9.2 Description of a monograph

Glossary

Bibliography

Index

Dedication

In loving memory of my father, who died very shortly after my mother, late in the process of writing this book, so never saw the project come to fruition!

花の色は

移りにけりな

いたづらに

わが身世にふる

ながめせしまに

(小野 小町)

Once-colorful flowers faded,

while in my drab cell

life’s impulse also abated

as the long dismal rains fell.

Ono no Komachi (825 – c. 900);

loose translation by Michael R. Burch

Copyright

First published 2018 in Great Britain and the United States by ISTE Press Ltd and Elsevier Ltd

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address:

ISTE Press Ltd

27-37 St George’s Road

London SW19 4EU

UK

www.iste.co.uk

Elsevier Ltd

The Boulevard, Langford Lane

Kidlington, Oxford, OX5 1GB

UK

www.elsevier.com

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability 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.

For information on all our publications visit our website at http://store.elsevier.com/

© ISTE Press Ltd 2018

The rights of Roland Barret to be identified as the author of this work have been asserted by him in accordance with the Copyright, Designs and Patents Act 1988.

British Library Cataloguing-in-Publication Data

A CIP record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book is available from the Library of Congress

ISBN 978-1-78548-288-5

Printed and bound in the UK and US

Preface

Professor Roland Barret April 2018

I would like to express my deepest thanks to my colleague and friend, Professor Nadia Walchshofer, who graciously took the time to read over this humble work. Her corrections and comments have been enormously helpful, and her eagle eye has been a real asset in this process – thanks again. My thanks also go to Professor Lomberget, who helped me with the complex task of pagesetting the manuscript! As I write this, I am reminded of Professor Daudon, to whom I owe, in no small measure, what I have become. I hope that he will look kindly upon this book, from his seat on high with the Cherubim of Chemistry.

Why have I written this book? Criticisms are continually being leveled at chemistry, especially in the study of pharmacy, where some authors claim that the discipline of chemistry is on its deathbed, saying that biotechnologies will be able to combat any and all diseases.

What will become of our discipline in a few years’ time, if students continue to be fed this propaganda? Hollow, meaningless words; a science without a solid foundation, performing superficial research which (mis)-uses poorly understood concepts. Thus, I hope, people will see the fundamental importance of chemistry for all of the different areas of pharmacy.

It is in this hope that I set out to pen this book, to give encouragement and direction where they are sorely lacking. One can always hope…

Below are a few choice statements of opinion about chemistry (from people such as journalists, scholars and philosophers).

J.P. Varlenge points out: life on Earth – as we know it – is inextricably linked to homochirality ¹ .

Marc Fontecave, professor at the Collège de France in Paris [FON 09], bemoans that fact that:

in France today – owing to: the increasingly utilitarian view taken of science by politicians; the archaism of the teaching in our universities; the rigidity of the structures of our research organizations; and finally the conservative stance of our businesses, despite the discourse (never before has there been so much said about the importance of the so-called ‘chemistry–biology interface’) – the yawning gap between chemistry and biology is, from where I stand, a long way from being bridged. On the other hand, I can bear witness to the joy, for a chemist, of thinking about life, and the untold worlds that are waiting to be discovered in that domain.

Finally, philosopher Michel Serre states ² :

As soon as we say that something is ‘chemical’, nowadays, it is automatically thought to be bad. People don’t realize that chemistry is everywhere: in our clothes, our most basic supplies, in cars, in household appliances, and so on. And beyond that, chemistry can save our very lives! Chemistry is pharmacy: anti-inflammatories, painkillers and more. Thanks to chemistry, numerous diseases have now been wiped out, or at least are treatable, and life expectancy has gone up. (…) but our brains, our knees, that piece of paper… it is all chemistry. Without chemistry, there would be no biology. People speak of ‘bio’ in opposition to ‘chemistry’, as though ‘bio’ means ‘without chemistry’… but bio is chemistry!

Will these words ring true with our students?

This book, then, is aimed at everyone who is interested in medicine: pharmacy students, of course, but also students on a variety of Masters courses (in the schools of pharmacy and science), taking classes that look at not only drug design, but also drug analysis, pharmacokinetics and, to a certain extent, clinical pharmacology.

---

¹ VieS des ScienceS, SociétéS, ArtS, La liberté commence où l’ignorance finit: https://www.jeanpierrevarlenge.com/).

² http://www.Ladepeche.fr/article/2011/09/21/1172459-la-chimie-c-est-la-vie.html; (http://www.lejdd.fr/Economie/Actualite/Serres-Ce-n-est-pas-une-crise-c-est-unchangement-de-monde-583645).

1

Medicines and Drugs

Abstract

The word medicine may be understood differently depending on the discipline at hand. For a chemist, the word corresponds to the active principle (the product responsible for the drug’s activity); for a galenist, it is the active principle and the excipients; for a pharmacist, it is the specialty (the commercial product). We encounter the same problem with the word "drug" which, for a chemist, also represents the active principle; for a pharmacognosy specialist, it is the extraction mixture; and for a galenist, it is the specialty.

Keywords

Anatomical Therapeutic Chemical; Base Claude Bernard; European Medicines Agency; International Union of Pure and Applied Chemistry; Pharmacological filters; Polar Surface Area; Temporary Authorization for Use; Thesorimed; Vidal Medical Dictionary; World Health Organization

1.1 Definition of a drug

The word medicine may be understood differently depending on the discipline at hand. For a chemist, the word corresponds to the active principle (the product responsible for the drug’s activity); for a galenist, it is the active principle and the excipients; for a pharmacist, it is the specialty (the commercial product). We encounter the same problem with the word "drug" which, for a chemist, also represents the active principle; for a pharmacognosy specialist, it is the extraction mixture; and for a galenist, it is the specialty.

Notwithstanding this ambiguity, from a chemist’s point of view, when we speak of drugs/medicines here, we mean the active principle. The usual definition of a drug is as follows:

Definition

A drug is a small molecule whose molar mass is generally between 100 and 1,000, which, when introduced into an organism’s system, alters its