SYNTHESIS AND ENZYMATIC-HYDROLYSIS OF ESTERS, CONSTITUTING SIMPLE-MODELS OF SOFT DRUGS

One way to minimise systemic side effects of drugs is to design molecu les, soft drugs, in such a way that they are metabolically inactivated rapidly after having acted on their pharmacological target. Hydrolase s (esterases, peptidases, Lipases, glycosidases, etc.) are enzymes wel l suited to use for drug inactivation since they are ubiquitously dist ributed. Insertion of ester bonds susceptible to enzymatic cleavage ma y represent one approach to make the action of a drug more restricted to the site of application. The present study describes the chemical s ynthesis of fourteen model compounds comprising a bicyclic aromatic un it connected by an ester-containing bridge to another aromatic ring. I nitial attempts to define a) the tissue selectivity of the hydrolytic metabolism and b) the molecular structural factors affecting the rate of enzymatic ester cleavage are presented. The data show that human an d rat liver fractions were more active than human duodenal mucosa and human blood leukocytes at hydrolysing the compounds. The rank order of the compounds was, however, very similar in the different biological systems. Commercially available pig liver carboxyl esterase and choles terol esterase both reasonably well predict the rank order in the tiss ue fractions.