4PYV

Crystal structure of renin in complex with compound4

4PYV の概要

• エントリーDOI: 10.2210/pdb4pyv/pdb
• 分子名称: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, tert-butyl {(3S,5R)-5-[cyclopropyl(2,3-dichlorobenzyl)carbamoyl]piperidin-3-yl}carbamate, ... (6 entities in total)
• 機能のキーワード: renin inhibitor, 3, 5-substituted piperidines, hydrolase inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens
• 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: 75970.44

構造登録者

Ostermann, N.,Zink, F. (登録日: 2014-03-28, 公開日: 2014-10-08, 最終更新日: 2024-11-27)

主引用文献

Ehara, T.,Irie, O.,Kosaka, T.,Kanazawa, T.,Breitenstein, W.,Grosche, P.,Ostermann, N.,Suzuki, M.,Kawakami, S.,Konishi, K.,Hitomi, Y.,Toyao, A.,Gunji, H.,Cumin, F.,Schiering, N.,Wagner, T.,Rigel, D.F.,Webb, R.L.,Maibaum, J.,Yokokawa, F.
Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.
ACS Med Chem Lett, 5:787-792, 2014

PubMed Abstract: A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

PubMed: 25050166
DOI: 10.1021/ml500137b

実験手法

X-RAY DIFFRACTION (2.65 Å)