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Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir
- Source :
- Journal of Medicinal Chemistry. 57:2013-2032
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 2014.
-
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.
- Subjects :
- Spectrometry, Mass, Electrospray Ionization
Magnetic Resonance Spectroscopy
Pyrrolidines
Daclatasvir
Hepatitis C virus
Hepacivirus
Viral Nonstructural Proteins
Pharmacology
Virus Replication
medicine.disease_cause
Antiviral Agents
Structure-Activity Relationship
Dogs
Pharmacokinetics
Drug Discovery
medicine
Animals
Structure–activity relationship
Replicon
Enzyme Inhibitors
NS5A
EC50
Chemistry
Drug discovery
Imidazoles
Valine
Virology
Rats
Area Under Curve
Molecular Medicine
Carbamates
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....ccb09c433565e97a1989a67acd31dde3