title: Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.
abstract: Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gising
authors.forename: Anna Karin
authors.initials: AK
authors.lastname: Belfrage
authors.forename: Hiba
authors.initials: H
authors.lastname: Alogheli
authors.forename: Angelica
authors.initials: A
authors.lastname: Ehrenberg
authors.forename: Eva
authors.initials: E
authors.lastname: Åkerblom
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
mesh_terms: D001665:Binding Sites; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases