Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor

[Image: see text] The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1′ site binder into the lead compound 1 guided by structure-based drug design (SBDD), and fur...

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Detalles Bibliográficos
Autores principales: Imaeda, Yasuhiro, Tokuhara, Hidekazu, Fukase, Yoshiyuki, Kanagawa, Ray, Kajimoto, Yumiko, Kusumoto, Keiji, Kondo, Mitsuyo, Snell, Gyorgy, Behnke, Craig A., Kuroita, Takanobu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066151/
https://www.ncbi.nlm.nih.gov/pubmed/27774132
http://dx.doi.org/10.1021/acsmedchemlett.6b00251
Descripción
Sumario:[Image: see text] The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1′ site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.

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