WATER-SOLUBLE RENIN INHIBITORS - DESIGN OF A SUBNANOMOLAR INHIBITOR WITH A PROLONGED DURATION OF ACTION

Incorporation of nonreactive polar functionalities at the C- and N-termini of renin inhibitors led to the development of a subnanomolar compound (21) with millimoiar solubility. This inhibitor demonstrated excellent efficacy and a long duration of action upon intravenous administration to monkeys. While activity was also observed intraduodenally, a comparison of the blood pressure responses indicated low bioavailability. Subsequent experiments in rats showed that, although the compound was absorbed from the gastrointestinal tract, extensive liver extraction severely limited bioavailability. © 1990, American Chemical Society. All rights reserved.