| Autor: |
Göschke R; Novartis Institutes for BioMedical Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland., Stutz S, Rasetti V, Cohen NC, Rahuel J, Rigollier P, Baum HP, Forgiarini P, Schnell CR, Wagner T, Gruetter MG, Fuhrer W, Schilling W, Cumin F, Wood JM, Maibaum J |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2007 Oct 04; Vol. 50 (20), pp. 4818-31. Date of Electronic Publication: 2007 Sep 08. |
| DOI: |
10.1021/jm070314y |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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