Prodrugs

ANDREW W.LLOYD and H.JOHN SMITH

CONTENTS

7.1 INTRODUCTION 236

7.2 PRO-DRUG DESIGN 240

7.3 APPLICATION TO PHARMACEUTICAL PROBLEMS 241

7.3.1 Patient acceptability 241

7.3.2 Drug solubility 242

7.3.3 Drug stability 243

7.4 PHARMACOLOGICAL PROBLEMS 245

7.4.1 Drug absorption 245

7.4.2 Drug distribution 250

7.4.3 Site-specific drug delivery 253

7.4.4 Sustaining drug action 258

7.5 SUMMARY 259 FURTHER READING 259

7.1 INTRODUCTION

Although pharmaceutical companies attempt to design and develop new chemical entities using rational and logical processes, very few of these compounds become clinically useful drugs because unpredictable interactions with biological systems reduces therapeutic efficacy and in many cases leads to undesirable toxicity. An alternative approach to enhance therapeutic activity relies on the chemical modification of known compounds to overcome the undesirable physical and chemical properties using pro-drug design.

A pro-drug is a pharmacacologically inactive compound which is metabolised to the active drug by either a chemical or enzymatic process. Some of the early pharmaceuticals were found to be pro-drugs and this has led to the subsequent introduction of the metabolite itself into therapy, particularly in cases where the active metabolite is less toxic or has fewer side effects than the parent pro-drug. The administration of the active metabolite may also reduce variability in clinical response between individuals which is attributed to differences in pharmacogenetics, particularly in disease states.

The earliest example of a pro-drug is arsphenamine (7.1) used by Ehrlich for the treatment of syphilis. Later Voegtlin demonstrated that the activity of this compound against the syphilis organism was attributable to the metabolite oxophenarsine (7.2). Arsphenamine was later replaced by oxophenarsine in therapy as the the metabolite was less toxic at the dose required for effective therapy.

Other such discoveries have led to the development of complete classes of drug compounds. For example the development of present day sulphonamide therapy evolved from the discovery by Domagk in 1935 that the azo dye prontosil (7.3) had antibacterial activity. Prontosil was subsequently shown to be a precursor which was metabolised to the active agent, p-aminobenezenesulphonamide (7.4), in vivo. This led to the subsequent development of a wide range of therapeutically superior sulphonamides through modification of the aminobenzenesulphonamide molecule.

(7.3); promo.iil <7.4j

The antimalarial drugs pamaquin (7.5) and paludrine (7.7) are also both converted to active metabolites by the body. Pamaquin is dealkylated and oxidised to the quinone (7.6) which is 16 times more active in vivo than the parent compound whereas paludrine cyclises to give the active dihydrotriazine (7.8) which has structural similarities to the active antimalarial pyrimethamine (7.9).

(7.3)
(7.4)

The dihydrotriazine metabolite, cycloguanil (7.8) has been administered as the insoluble pamoate salt in an oily base through a single intramuscular injection to provide malarial protection for up to several months depending on the particular particle size of the drug substance.

During the development of depressants trichloroethanol (7.11) was shown to be the active metabolite of the once used hypnotic chloral hydrate (Noctec®) (7.10). This led to the use of trichloroethanol acid phosphate (7.12) for patients where choral hydrate was found to be either unpalatable or caused gastric irritation.

CljC—CH(OHXi (7.10); chkiral hytlralc

GjC -CHjOH (7.11); trichloroelhano]

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