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

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z