Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease

Bioorg Med Chem. 2016 Jun 15;24(12):2603-20. doi: 10.1016/j.bmc.2016.03.066.

Anna Karin Belfrage ¹, Eldar Abdurakhmanov ², Eva Kerblom ¹, Peter Brandt ¹, Anna Oshalim ¹, Johan Gising ¹, Anna Skogh ¹, Johan Neyts ³, U Helena Danielson ², Anja Sandström ⁴

Affiliations

1 Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
2 Department of Chemistry-BMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden.
3 Rega Institute, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium.
4 Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden. Electronic address: anja.sandstrom@orgfarm.uu.se.

PMID: 27160057 DOI: 10.1016/j.bmc.2016.03.066

Abstract

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 Protease Inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wild-type and the drug resistant Enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 Protease Inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

Keywords

Drug resistance; Hepatitis C virus; NS3 protease inhibitors; Pyrazinone; R155K.

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