Patent Evaluation: Amino acid pro-drugs as RAS inhibitors

Abstract

Novelty: Novel amino acid prodrugs, said to have renin inhibitory activity and good aqueous solubility, are disclosed. The compounds are said to undergo selective, enzyme catalysed cleavage at the gut wall, resulting in increased local concentration and absorption. It is proposed that such compounds have greater bioavailability than presently known renin inhibitors and are said to have potential utility for the treatment of conditions such as hypertension, hyperaldosteronism, congestive heart failure and glaucoma.

Biology: In vitro studies evaluating stability of novel compounds in rat intestinal perfusate (IP) and suspensions of rat brush border membranes (BBM), respectively, are described. An exemplified compound was found to have respective tlI2 values of 508.5 and 514.0 minutes, in IP and BBM (analysed by HPLC). This is said to demonstrate that compounds of the invention are prodrugs, activated by gut wall enzymes.

Chemistry: The compound below is exemplified in the biological study. Preparative details using standard techniques, are presented.