5KOQ

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

5KOQ の概要

• エントリーDOI: 10.2210/pdb5koq/pdb
• 関連するPDBエントリー: 5KOS 5KOT
• 分子名称: 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)
• 機能のキーワード: protein-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted: P00797
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75254.84

構造登録者

Snell, G.P.,Behnke, C.A.,Okada, K.,Hideyuki, O.,Sang, B.-C.,Lane, W. (登録日: 2016-07-01, 公開日: 2016-11-02, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.7 Å)