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

Authors :
Imaeda Y
Tokuhara H
Fukase Y
Kanagawa R
Kajimoto Y
Kusumoto K
Kondo M
Snell G
Behnke CA
Kuroita T
Source :
ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Sep 12; Vol. 7 (10), pp. 933-938. Date of Electronic Publication: 2016 Sep 12 (Print Publication: 2016).
Publication Year :
2016

Abstract

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 -[(3 S ,5 R )-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1 H- 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.

Details

Language :
English
ISSN :
1948-5875
Volume :
7
Issue :
10
Database :
MEDLINE
Journal :
ACS medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
27774132
Full Text :
https://doi.org/10.1021/acsmedchemlett.6b00251