Design Of Enzyme Inhibitors As Drugs

ANJANA PATEL, H.JOHN SMITH and JORG STURZEBECHER

CONTENTS

8.1 INTRODUCTION 262

8.1.1 Basic concept 262

8.1.2 Types of inhibitors 264

8.2 GENERAL ASPECTS OF INHIBITOR DESIGN 271

8.2.1 Target enzyme and inhibitor selection 271

8.2.2 Specificity and toxicity 273

8.3 RATIONAL APPROACH TO THE DESIGN OF ENZYME INHIBITORS 275

8.4 DEVELOPMENT OF A SUCCESSFUL DRUG FOR

THE CLINIC 277

8.4.1 Oral absorption 278

8.4.2 Metabolism 279

8.4.3 Toxicity 281

8.5 STEREOSELECTIVITY 281

8.6 EXAMPLES OF ENZYME INHIBITORS AS

DRUGS 283

8.6.1 Protease inhibitors 283

8.6.1.1 Serine proteases 284

8.6.1.2 Metallo-proteases 299

8.6.1.3 Aspartate proteases 309

8.6.2 Acetylcholinesterase inhibtors 317

8.6.3 Aromatase inhibitors 320

8.6.4 Pyridoxal phosphate—dependent enzyme inhibitors 322

8.6.4.1 GABA transaminase (GABA-T) inhibitors 325

8.6.4.2 Peripheral aromatic amino acid decarboxylase (AADC) inhibitors 327

8.6.4.3 Ornithine decarboxylase (ODC) inhibitors 329 FURTHER READING 330

8.1 INTRODUCTION

Enzymes catalyse the reactions of their substrates by initial formation of a complex (ES) between the enzyme and substrate(S) at the active site of the enzyme. This complex then breaks down, either directly of through intermediary stages, to give the products (P) of the reaction with regeneration of the enzyme:

kcat is the overall rate constant for decomposition of ES into products, k2 and k3 are the respective rate constants for formation and breakdown of the intermediate E' (i.e. kcat= kk/k+kj)). Chemical agents, known as inhibitors, modify the ability of an enzyme to catalyse the reaction of its substrates. The term inhibitor is usually restricted to chemical agents, other modifiers of enzyme activity such as pH, ultra-violet light and heat being known as denaturising agents.

8.1.1 Basic concept

The body contains several thousand different enzymes each catalysing a reaction of a single substrate or group of substrates. An array of enzymes is involved in a metabolic pathway, each catalysing a specific step in the pathway, i.e.

These actions are integrated and controlled in various ways to produce a coherent pattern governed by the requirements of the cell.

The basis for using enzyme inhibitors as drugs is that inhibition of a suitably selected target enzyme leads firstly to a build-up in concentration of substrate(s) and secondly to a corresponding decrease in concentration of the metabolite(s), one of which leads to a useful clinical response. Where the substrate gives a required response (i.e. agonist) inhibition of a degradative enzyme leads to accumulation of the substrate and accentuation of that response. Build up of acetylcholine by inhibition of acetylcholinesterase using neostigmine is used for the treatment of myasthenia gravis and glaucoma (Equation [8.3]).

CH^COOCHjCHjNiCHOj --CH,COOH + HOCH,CH;NffCH;),

Where the metabolite has an action judged to be clinically undesirable or too pronounced, then enzyme inhibition reduces its concentration with a decreased (desired) response. Allopurinol is an inhibitor of xanthine oxidase and is used for the treatment of gout. The inhibition of the enzyme decreases conversion of the purines xanthine and hypoxanthine to uric acid, which otherwise deposits and produces irritation in the joints (Equation [8.4]).

In the above example an enzyme acting in isolation was targeted but several other strategies may be used with enzyme inhibitors to produce an overall satisfactory clinical response. The target enzyme may be part of a biosynthetic pathway consisting of a sequence of enzymes with their specific substrates and co-enzymes (Equation [8.5]). Here the aim is to prevent, by the careful selection of the target enzyme in the pathway (see Section 8.2.1), the overall production of a metabolite which either clinically gives an unrequired response or is essential to bacterial or cancerous growth.

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