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1.
Bioorg Med Chem Lett ; 25(5): 1140-5, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25599836

ABSTRACT

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients.


Subject(s)
Acrylates/chemistry , Acrylates/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Indoles/chemistry , Indoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Acrylates/pharmacokinetics , Acrylates/toxicity , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Dogs , Haplorhini , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Indoles/pharmacokinetics , Indoles/toxicity , Lipids/chemistry , Liver/metabolism , Liver/virology , Rats , Viral Nonstructural Proteins/metabolism
2.
J Med Chem ; 57(5): 2013-32, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24521299

ABSTRACT

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Area Under Curve , Carbamates , Dogs , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , Hepacivirus/physiology , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Magnetic Resonance Spectroscopy , Pyrrolidines , Rats , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Valine/analogs & derivatives
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