10LR

N-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable PlasmaKallikrein Inhibitors complex with Compound 4 ((3'R)-1'-(5-amino-1-benzyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one)

これはPDB形式変換不可エントリーです。

10LR の概要

• エントリーDOI: 10.2210/pdb10lr/pdb
• 関連するPDBエントリー: 10KZ
• 分子名称: Plasma kallikrein, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (3'R)-1'-(5-amino-1-benzyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one, ... (5 entities in total)
• 機能のキーワード: hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31768.19

構造登録者

Merchant, R.R.,Chernyak, N.,Lopez, J.A.,Sharp, P.P.,Mandal, M.,He, J.,Hruza, A.,Rearden, P.,Tatosian, D.A.,Lin, K.,Esmay, J.,Yang, S.,Cheng, A.,Ellsworth, K.,Piou, T.,Fier, P.,Hicks, J.,Sinz, C.,Ogawa, A. (登録日: 2026-01-27, 公開日: 2026-03-11, 最終更新日: 2026-04-01)

主引用文献

Merchant, R.R.,Chernyak, N.,Lopez, J.A.,Sharp, P.P.,Mandal, M.,He, J.,Hruza, A.,Rearden, P.,Tatosian, D.A.,Esmay, J.,Yang, S.,Cheng, A.C.,Ellsworth, K.,Ogawa, A.,Piou, T.,Fier, P.,Hicks, J.,Sinz, C.,Ogawa, A.K.
N ‐Alkyl and N ‐Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors.
Acs Med.Chem.Lett., 17:744-749, 2026

PubMed Abstract: Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabetic mellitus complications, and cerebrovascular disorders. As part of an internal program to develop orally bioavailable small-molecule pKal inhibitors, we report lead optimization efforts within the spirocarbamate scaffold, highlighting a structure-based drug design strategy to engineer hydrogen bond interactions with -benzyl aminopyrazoles. Additionally, mitigation of time-dependent inhibition (TDI) liability and optimization of the overall profile were achieved through a two-pronged strategy: (1) incorporating increased Fsp modifications via -alkylation and (2) leveraging torsional strain in -aryl analogs.

PubMed: 41847638
DOI: 10.1021/acsmedchemlett.6c00066

実験手法

X-RAY DIFFRACTION (1.583 Å)