3Q4B

Clinically Useful Alkyl Amine Renin Inhibitors

3Q4B の概要

• エントリーDOI: 10.2210/pdb3q4b/pdb
• 関連するPDBエントリー: 3GW5 3KM4 3Q3T 3Q5H
• 分子名称: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: aspartate protease, hypertension, renin expression, renin inhibitor, aspartyl protease, cleavage on pair of basic residues, glycoprotein, membrane, protease, secreted, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76018.10

構造登録者

Wu, Z.,McKeever, B.M. (登録日: 2010-12-23, 公開日: 2011-11-30, 最終更新日: 2024-10-16)

主引用文献

Jia, L.,Simpson, R.D.,Yuan, J.,Xu, Z.,Zhao, W.,Cacatian, S.,Tice, C.M.,Guo, J.,Ishchenko, A.,Singh, S.B.,Wu, Z.,McKeever, B.M.,Bukhtiyarov, Y.,Johnson, J.A.,Doe, C.P.,Harrison, R.K.,McGeehan, G.M.,Dillard, L.W.,Baldwin, J.J.,Claremon, D.A.
Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
ACS Med Chem Lett, 2:747-751, 2011

PubMed Abstract: Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

PubMed: 24900262
DOI: 10.1021/ml200137x

実験手法

X-RAY DIFFRACTION (2.19 Å)