Department of Pharmacy, GRD Institutes, India
*Corresponding author:Mohammad Asif, Department of Pharmacy, GRD Institutes, India
Submission: October 10, 2017; Published: July 05, 2018
ISSN : 2576-9170Volume2 Issue2
Activities of pyridazinones as inhibitors of the hepatitis C viral polymerase. These pyridazinones bind to the hepatitis C virus non-structural protein 5B (NS5B). Hepatitis C virus (HCV) RNA-dependent RNA polymerase, referred to as non-structural protein 5B (NS5B), is responsible for replication of the viral genome and is essential in the life cycle of the virus. Recently, active-site and allosteric NS5B inhibitors have appeared. Some 3(2H)-pyridazinones exhibited potent activity as inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their Drug Metabolism and Pharmacokinetics (DMPK) profiles. It has long been considered an attractive target for the development of direct acting antiviral (DAA) agents. This investigation led to the discovery of potent inhibitors with improved DMPK properties which displayed potent inhibitory activities, good stability toward human liver microsomes, and high ratios of liver to plasma concentrations. In vitro DMPK data for many of the compounds are disclosed and a crystal structure of a representative inhibitor complexed with the NS5B protein.
Keywords: Antiviral agents; NS5B polymerase; HIV-1 reverse transcriptase; Pyridazinones; Hepatitis C virus; RNA-dependent; RNA polymerase; NS5B inhibitors; DMPK profiling
Abbreviations: NS5B: Non-Structural Protein 5B; HCV: Hepatitis C Virus; DMPK: Drug Metabolism and Pharmacokinetics; DAA: Direct Acting Antiviral; RDRP: RNA-Dependent RNA Polymerase; Peg-IFN: Pegylated Interferon; RBV: Ribavirin; HLM: Human Liver Microsomes; MLM: Monkey Liver Microsomes