ABSTRACT
Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.
Subject(s)
Antiviral Agents/pharmacology , Carbamates/chemistry , Drug Discovery , Hepacivirus/drug effects , Heterocyclic Compounds, 4 or More Rings/chemistry , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Protease Inhibitors/pharmacology , Sofosbuvir/chemistry , Sulfonamides/chemistry , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Aminoisobutyric Acids , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cyclopropanes , Dose-Response Relationship, Drug , Drug Combinations , Hepacivirus/genetics , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Macrocyclic Compounds/chemical synthesis , Microbial Sensitivity Tests , Molecular Structure , Proline/analogs & derivatives , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Quinoxalines , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.
Subject(s)
Carbamates/chemistry , Cytochrome P-450 CYP3A Inhibitors , Diamines/chemistry , Diamines/pharmacology , Thiazoles/chemistry , Carbamates/pharmacology , Cobicistat , Enzyme Activation/drug effects , Molecular Structure , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.
