Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin

Background: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in th e conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural inf ormation concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that inte ract with the large hydrophobic S1/S3-binding pocket in renin. Results: Crystal structure analysis of renin-inhibitor complexes combined w ith computational methods were employed in the medicinal-chemistry optimisa tion process. Structure analysis revealed that the newly designed inhibitor s bind as predicted to the S1/S3 pocket. In addition, however, these compou nds interact with a hitherto unrecognised large, distinct, sub-pocket of th e enzyme that extends from the S3-binding site towards the hydrophobic Gore of the enzyme. Binding to this S3(sp) sub-pocket was essential for high bi nding affinity. This unprecedented binding mode guided the drug-design proc ess in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. Conclusions: Our design approach led to compounds with high in vitro affini ty and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors ar e therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.