10MV

N-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors complex with Compound 15 ((3'R)-1'-(5-amino-1-phenyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one)

This is a non-PDB format compatible entry.

Summary for 10MV

• Entry DOI: 10.2210/pdb10mv/pdb
• Related: 10KZ 10LR
• Descriptor: Plasma kallikrein, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (3'R)-1'-(5-amino-1-phenyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one, ... (5 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 31754.16

Authors

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.,Ogawa, A.,Piou, T.,Fier, P.,Hicks, J.,Sinz, C.,Ogawa, A. (deposition date: 2026-01-28, release date: 2026-04-01)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.66 Å)