Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors

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• 作者：Olivier Bezenon ; Daniel Bur ; Thomas Weller ; Sylvia Richard-Bildstein ; Lubo Reme ; Thierry Sifferlen ; Olivier Corminboeuf ; Corinna Grisostomi ; Christoph Boss ; Lars Prade ; Stphane Delahaye ; Alexander Tre
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 25, 2009
• 年：2009
• 卷：52
• 期：12
• 页码：3689-3702
• 全文大小：315K
• 年卷期：v.52,no.12(June 25, 2009)
• ISSN：1520-4804

文摘

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 IC₅₀ 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.