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Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors

2009; American Chemical Society; Volume: 52; Issue: 12 Linguagem: Inglês

10.1021/jm900022f

1520-4804

Olivier Bezençon, Daniel Bur, Thomas Weller, Sylvia Richard‐Bildstein, Luboš Remeň, Thierry Sifferlen, Olivier Corminboeuf, Corinna Grisostomi, Christoph Boss, Lars Prade, Stéphane Delahaye, Alexander Treiber, Panja Strickner, Christoph A. Binkert, Patrick Hess, Beat Steiner, Walter Fischli,

Hormonal Regulation and Hypertension

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.