title: Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP3 Receptor Antagonists.
abstract: High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Angel
authors.initials: A
authors.lastname: Morales-Ramos
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Patrick
authors.initials: P
authors.lastname: Eidam
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: John
authors.initials: J
authors.lastname: Mecom
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Carl
authors.initials: C
authors.lastname: Brooks
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Mark
authors.initials: M
authors.lastname: Hilfiker
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Dongchuan
authors.initials: D
authors.lastname: Shi
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Pei-San
authors.initials: PS
authors.lastname: Tseng
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Karen
authors.initials: K
authors.lastname: Wheless
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Brian
authors.initials: B
authors.lastname: Budzik
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Karen
authors.initials: K
authors.lastname: Evans
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Jon-Paul
authors.initials: JP
authors.lastname: Jaworski
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Jack
authors.initials: J
authors.lastname: Jugus
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Lisa
authors.initials: L
authors.lastname: Leon
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Charlene
authors.initials: C
authors.lastname: Wu
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Mark
authors.initials: M
authors.lastname: Pullen
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Bhumika
authors.initials: B
authors.lastname: Karamshi
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Parvathi
authors.initials: P
authors.lastname: Rao
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Emma
authors.initials: E
authors.lastname: Ward
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Laping
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Christopher
authors.initials: C
authors.lastname: Evans
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Colin
authors.initials: C
authors.lastname: Leach
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Dennis
authors.initials: D
authors.lastname: Holt
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Dwight
authors.initials: D
authors.lastname: Morrow
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Harvey
authors.initials: H
authors.lastname: Fries
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Kevin
authors.initials: K
authors.lastname: Thorneloe
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
authors.forename: Richard
authors.initials: R
authors.lastname: Edwards
keywords: 3-oxazolidinedione-6-aryl-pyridinones; EP3 receptor; novel, potent, selective, and orally active antagonists