Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead

  • J Med Chem. 2024 Feb 22;67(4):2369-2378. doi: 10.1021/acs.jmedchem.3c01938.
N G R Dayan Elshan  1 ,  Karen C Wolff  1 ,  Laura Riva  1 ,  Ashley K Woods  1 ,  Gennadii Grabovyi  1 ,  Katy Wilson  1 ,  James Pedroarena  1 ,  Sourav Ghorai  1 ,  Armen Nazarian  1 ,  Frank Weiss  1 ,  Yuyin Liu  1 ,  Wrickban Mazumdar  1 ,  Lirui Song  1 ,  Neechi Okwor  1 ,  Jacqueline Malvin  1 ,  Malina A Bakowski  1 ,  Nathan Beutler  2 ,  Melanie G Kirkpatrick  1 ,  Amal Gebara-Lamb  1 ,  Edward Huang  1 ,  Vân T B Nguyen-Tran  1 ,  Victor Chi  1 ,  Shuangwei Li  1 ,  Thomas F Rogers  2 ,  Case W McNamara  1 ,  Anil Kumar Gupta  1 ,  Alireza Rahimi  1 ,  Jian Jeffrey Chen  1 ,  Sean B Joseph  1 ,  Peter G Schultz  1  3 ,  Arnab K Chatterjee  1
Affiliations
  • 1. Calibr at Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
  • 2. Department of Immunology and Microbiology, The Scripps Research Institute, 10466 North Torrey Pines Road, La Jolla, California 92037, United States.
  • 3. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
PMID: 38335279 DOI: 10.1021/acs.jmedchem.3c01938
Abstract

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

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