title: Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease.
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.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
authors.forename: Anna Karin
authors.initials: AK
authors.lastname: Belfrage
authors.affiliation: Department of Chemistry-BMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden.
authors.forename: Eldar
authors.initials: E
authors.lastname: Abdurakhmanov
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kerblom
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Brandt
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Oshalim
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gising
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Skogh
authors.affiliation: Rega Institute, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Chemistry-BMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden.
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden. Electronic address: anja.sandstrom@orgfarm.uu.se.
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D062105:Molecular Docking Simulation; D017354:Point Mutation; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D011719:Pyrazines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: Drug resistance; Hepatitis C virus; NS3 protease inhibitors; Pyrazinone; R155K