title: Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors.
abstract: Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Barnes-Seeman
authors.affiliation: Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Carri
authors.initials: C
authors.lastname: Boiselle
authors.affiliation: Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Capacci-Daniel
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Hoffmaster
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Jones
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Sue
authors.initials: S
authors.lastname: Ma
authors.affiliation: Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Pan
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Shu
authors.affiliation: Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Leah
authors.initials: L
authors.lastname: Whiteman
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States. Electronic address: jiping.fu@novartis.com.
authors.forename: Jiping
authors.initials: J
authors.lastname: Fu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D007769:Lactams / Q000737:chemistry; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007769:Lactams; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: CYP induction; HCV; Lactam; NS5B polymerase; PXR; Thiophene