2. Academic Validation
  3. N‑Alkyl and N‑Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors

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

  • ACS Med Chem Lett. 2026 Feb 24;17(3):744-749. doi: 10.1021/acsmedchemlett.6c00066.
Rohan R Merchant 1,  Natalia Chernyak 1,  Jovan A Lopez 1,  Phillip P Sharp 1,  Mihir Mandal 2,  Jiafang He 2,  Alan Hruza 2,  Paul Rearden 3,  Daniel A Tatosian 4,  Joel Esmay 3,  Song Yang 5,  Alan C Cheng 5,  Ken Ellsworth 6,  Aimie Ogawa 7,  Tiffany Piou 8,  Patrick Fier 8,  Jacqueline Hicks 2,  Christopher Sinz 1,  Anthony K Ogawa 1
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 2 Department of Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 3 Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 4 Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 5 Computational and Structural Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 6 Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 7 Quantitative Biosciences, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 8 Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
PMID: 41847638 DOI: 10.1021/acsmedchemlett.6c00066
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 Fsp3 modifications via N-alkylation and (2) leveraging torsional strain in N-aryl analogs.

Keywords

Fsp3; H-Bond; Lead Optimization; Structure-Based Drug Design (SBDD); TDI; Torsional Angles; pKal.

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