title: Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A.
abstract: Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional 'E' ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.
authors: Research and Development, AbbVie Inc., North Chicago, IL 60064, USA. david.degoey@abbvie.com
authors: David A
authors: DA
authors: DeGoey
authors: David A
authors: DA
authors: Betebenner
authors: David J
authors: DJ
authors: Grampovnik
authors: Dachun
authors: D
authors: Liu
authors: John K
authors: JK
authors: Pratt
authors: Michael D
authors: MD
authors: Tufano
authors: Wenping
authors: W
authors: He
authors: Preethi
authors: P
authors: Krishnan
authors: Tami J
authors: TJ
authors: Pilot-Matias
authors: Kennan C
authors: KC
authors: Marsh
authors: Akhteruzzaman
authors: A
authors: Molla
authors: Dale J
authors: DJ
authors: Kempf
authors: Clarence J
authors: CJ
authors: Maring
mesh_terms: D055808:Drug Discovery; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D011743:Pyrimidines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase