5KOQ

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

Summary for 5KOQ

• Entry DOI: 10.2210/pdb5koq/pdb
• Related: 5KOS 5KOT
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-~{tert}-butyl-4-(furan-2-ylmethylamino)-~{N}-(2-methylpropyl)-~{N}-[(3~{S})-piperidin-3-yl]pyrimidine-5-carboxamide, ... (5 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: 75254.84

Authors

Snell, G.P.,Behnke, C.A.,Okada, K.,Hideyuki, O.,Sang, B.-C.,Lane, W. (deposition date: 2016-07-01, release date: 2016-11-02, Last modification date: 2024-10-23)

Primary citation

Imaeda, Y.,Tawada, M.,Suzuki, S.,Tomimoto, M.,Kondo, M.,Tarui, N.,Sanada, T.,Kanagawa, R.,Snell, G.,Behnke, C.A.,Kubo, K.,Kuroita, T.
Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors.
Bioorg.Med.Chem., 24:5771-5780, 2016

PubMed Abstract: The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 ('Leu-in' to 'Leu-out') by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.

PubMed: 27687967
DOI: 10.1016/j.bmc.2016.09.030

Experimental method

X-RAY DIFFRACTION (2.7 Å)