title: Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema.
abstract: High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hilfiker
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Tram H
authors.initials: TH
authors.lastname: Hoang
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Johan
authors.initials: J
authors.lastname: Cornil
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Eidam
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Matasic
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Roethke
authors.affiliation: Platform Technology and Science, Molecular Discovery Research, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Klein
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Thorneloe
authors.affiliation: Departments of Chemistry, Biology, and Drug Metabolism and Pharmacokinetics, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
keywords: TRPV4; benzimidazole; calcium channel; heart failure; ion channel; pulmonary edema; transient receptor potential; vanilloid receptor