Nissim Claude Cohen

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 the 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 information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.

Design and synthesis of novel 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides as in vitro potent peptidomimetic inhibitors of human renin

Abstract Novel low-molecular weight transition-state peptidomimetic renin inhibitors characterized by an all-carbon 8-phenyl substituted octanecarboxamide skeleton have been discovered based on a topographical design approach. The in vitro most potent inhibitors 21, 25 and 26 incorporating a strong H-bond acceptor group linked to the benzyl spacer of the (P3-P1)-unit had IC50s in the low nanomolar range against human renin.

Generation of new-lead structures in computer-aided drug design

New and powerful tools are going to alter the perspectives of drug design in the near future. Impressive advances have recently been made in providing automated methods for lead finding in drug design. The spectacular progress made in both computational power and extensive data-storage capacity has made it possible to conceive very ambitious projects directed at lead finding in rational drug design. Computational capacity and memory are no longer limiting factors. Million of operations can be envisaged to process, retrieve, store and verify the structural capabilities of candidate molecules before lead structures conforming to the desired profile are identified and displayed. The aim of this article is to review existing approaches in the design of new lead structures, and to critically discuss some of the trends likely to emerge in the future in this relatively new discipline.