Synfacts 2020; 16(06): 0713
DOI: 10.1055/s-0040-1706957
Chemistry in Medicine and Biology
© Georg Thieme Verlag Stuttgart · New York

α-Ketoamide Inhibitors of SARS-CoV-2 Main Protease

Dirk Trauner
Christopher J. Arp
Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. * University of Lübeck, Germany
Crystal Structure of SARS-CoV-2 Main Protease Provides a Basis for Design of Improved α-Ketoamide Inhibitors.

Science 2020;
368: 409-412
Further Information

Publication History

Publication Date:
15 May 2020 (online)



SARS-CoV-2 is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Potent, broad-spectrum α-ketoamide inhibitors of the main protease (Mpro) of betacoronaviruses and alphacoronaviruses were recently reported by Hilgenfeld and co-workers (J. Med. Chem. 2020, DOI: 10.1021/acs.jmedchem.9b01828). X-ray crystallography and structure-based design led to the discovery of submicromolar α-ketoamide inhibitor 13b, which has now been developed specifically against SARS-CoV-2 Mpro to shut down the processing of polyproteins translated from viral RNA.



Starting from commercially available (R)-2-amino-3-cyclopropylpropanoic acid, Boc-protected pyridone D is synthesized in four steps. γ-Lactam B, a proxy for glutamine, is made using an asymmetric dianionic cyanomethylation of N-Boc-l-(+)-glutamic acid dimethyl ester (Q. Tian et al. Tetrahedron Lett. 2001, 42, 6807) and is coupled to the hydrolysis product of D. Five additional transformations yield 13b, which inhibits SARS-CoV-2 Mpro with IC50 = 0.67±0.18 μM and displays promising lung tropism and inhalation tolerance in mice.