Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead
N. G. R. Dayan Elshan, Karen C. Wolff, Laura Riva, Ashley K. Woods, Gennadii A. Grabovyi, Katy Wilson, James Pedroarena, Sourav Ghorai, Armen Nazarian, Frank Ulrich Weiß, Yuyin Liu, Wrickban Mazumdar, Lirui Song, Neechi Okwor, Jacqueline Malvin, Malina A. Bakowski, Nathan Beutler, Melanie G. Kirkpatrick, Amal Gebara-Lamb, Edward Huang, Vân Nguyên-Trân, Victor Chi, Shuangwei Li, Thomas F. Rogers, Case W. McNamara, Anil K. Gupta, Alireza Rahimi, Jian Jeffrey Chen, Sean B. Joseph, Peter G. Schultz, Arnab K. Chatterjee
Abstract
High Resolution Image Download MS PowerPoint Slide 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 (M pro, 3CL pro ) 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 3CL pro 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.