DESIGN AND SYNTHESIS OF NOVEL POTENT, NON-PEPTIDE AND ORALLY ACTIVE RENIN INHIBITORS. M. Grütter, J. Maibaum, V. Rasetti, H. Rüeger, R. Göschke, R. Mah, N.C. Cohen, J. Rahuel, F. Cumin, J. Wood, Ciba-Geigy Ltd. Pharmaceuticals Division, Research Dept., CH-4002 Basel, Switzerland

The renin-angiotensis system (RAS) plays a central role in the regulation of blood pressure and in the maintenance of electrolyte balance. In an effort to identify potent small molecule renin inhibitors with good oral bioavailabilityand duration of action we have developed a novel structural concept for the design of inhibitors as potential antihypertensive agents.

Our approach was based on the observation that the S3 and S1 binding sites of renin consitute a large continuous, hydrophobic `superpocket'. Initially, d-amino-hydroxyethylene dipeptide transition state mimics containing a lipophilic P3 moiety covalently linked to P1 via a spacer group were prepared and found to have moderate in vitro potency, although these inhibitors lacked the P4/P2 spanning part of peptide-based inhibitors. These results confirmed the hydrothesis that optimized van der Waals interactions of a hydrophobic (P3-linker-P1)-moiety with the large hydrophobic surface of the complementary binding site could compensate for truncation of the 219 of the enzyme, to the P3-P1 template of these leads dramatically increased in vitro potency and afforded inhibitors with subnanomolar IC₅₀ values and with high species and enzyme specificity. The iterative optimization process with the assistance of computer-aided molecular modelling and x-ray crystallographic analysis of r-human renin-inhibitor complexes revealed an intriguing common binging interaction of the new compounds to an hitherto unknown non substrate binding site of the renin. Synthesis and SAR data for structually distinct series of inhibitors with favorable physico chemical properties will be presented. In vivo, the most potent compounds, CGP 55 128A and CGP 56 346A, induced pronounce and long-lasting blood pressure effects at 1-10 mg/kg p.o. In Na-depleted marmosets.

In summary, the conceptual design described in the present study has led to discovery of completely non-peptide, highly selective and low molecular weight inhibitors of renin with unique structural features.