Preclinical characterization of the novel hepatitis C virus NS3 protease inhibitor GS-9451.
GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including in vitro antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC50s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC50 = 316 nM). Additive to synergistic in vitro antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ∼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.
Gilead Sciences, Foster City, California, USA.
Huiling
H
Yang
Margaret
M
Robinson
Amoreena C
AC
Corsa
Betty
B
Peng
Guofeng
G
Cheng
Yang
Y
Tian
Yujin
Y
Wang
Rowchanak
R
Pakdaman
Marian
M
Shen
Xiaoping
X
Qi
Hongmei
H
Mo
Chin
C
Tay
Steve
S
Krawczyk
X Christopher
XC
Sheng
Choung U
CU
Kim
Chris
C
Yang
William E
WE
Delaney
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005449:Fluorenes / Q000494:pharmacology; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000494:pharmacology; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012093:Replicon / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D016898:Interferon-alpha; D011480:Protease Inhibitors; D011687:Purines; D011724:Pyridazines; D011804:Quinolines; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C573362:GS-9451; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C586541:ledipasvir; C571890:tegobuvir