5KOS

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

Summary for 5KOS

• Entry DOI: 10.2210/pdb5kos/pdb
• Related: 5KOQ 5KOT
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-~{tert}-butyl-4-(3-methoxypropylamino)-~{N}-(2-methylpropyl)-~{N}-[(3~{S},5~{R})-5-morpholin-4-ylcarbonylpiperidin-3-yl]pyrimidine-5-carboxamide, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76458.68

Authors

Snell, G.P.,Behnke, C.A.,Okada, K.,Hideyuki, O.,Sang, B.-C.,Lane, W. (deposition date: 2016-07-01, release date: 2016-11-16, Last modification date: 2024-11-13)

Primary citation

Imaeda, Y.,Tokuhara, H.,Fukase, Y.,Kanagawa, R.,Kajimoto, Y.,Kusumoto, K.,Kondo, M.,Snell, G.,Behnke, C.A.,Kuroita, T.
Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.
Acs Med.Chem.Lett., 7:933-938, 2016

PubMed 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 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative (1-(4-methoxybutyl)--(2-methylpropyl)--[(3,5)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound is currently in clinical trials.

PubMed: 27774132
DOI: 10.1021/acsmedchemlett.6b00251

Experimental method

X-RAY DIFFRACTION (2.41 Å)