173399-55-8Relevant articles and documents
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
G?schke, Richard,Stutz, Stefan,Rasetti, Vittorio,Cohen, Nissim-Claude,Rahuel, Joseph,Rigollier, Pascal,Baum, Hans-Peter,Forgiarini, Peter,Schnell, Christian R.,Wagner, Trixie,Gruetter, Markus G.,Fuhrer, Walter,Schilling, Walter,Cumin, Frédéric,Wood, Jeanette M.,Maibaum, Jürgen
, p. 4818 - 4831 (2008/03/13)
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.
