N -Alkyl and N -Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors

ACS Medicinal Chemistry Letters 2026 Open access

Read full text
Authors: Rohan R. Merchant, Natalia Chernyak, Jovan A. Lopez, Phillip P. Sharp, Mihir Mandal, Jiafang He, Alan W. Hruza, Paul Rearden, Daniel A. Tatosian, Joel Esmay, Song Yang, Alan C. Cheng
+9 more Ken Ellsworth, Aimie M. Ogawa, Aimie M. Ogawa, Tiffany Piou, Patrick S. Fier, Jacqueline D. Hicks, Christopher J. Sinz, Anthony K. Ogawa, Anthony K. Ogawa
DOI: 10.1021/acsmedchemlett.6c00066
Cited by: 1
References: 17

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 N -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 3 modifications via N -alkylation and (2) leveraging torsional strain in N -aryl analogs.

Fields of Study & Subjects

Coagulation Bradykinin Polyphosphates and Angioedema Renin-Angiotensin System Studies Complement system in diseases

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
3
Pages
744–749
Publication date
24 February 2026
Language
EN