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Novel 2,7-Dialkyl-Substituted 5( S )-Amino-4( S )-hydroxy-8-phenyl-octanecarboxamide Transition State Peptidomimetics Are Potent and Orally Active Inhibitors of Human Renin

2007; American Chemical Society; Volume: 50; Issue: 20 Linguagem: Inglês

10.1021/jm070314y

1520-4804

Richard Göschke, Stefan Stutz, Vittorio Rasetti, Nissim-Claude Cohen, Joseph Rahuel, Pascal Rigollier, Hans-Peter Baum, Peter Forgiarini, Christian Schnell, Trixie Wagner, M.G. Gruetter, Walter Fuhrer, Walter Schilling, Frédéric Cumin, Jeanette M. Wood, Jürgen Maibaum,

Computational Drug Discovery Methods

The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.