title: Structure-activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists.
abstract: Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. amramos@vitaerx.com
authors.forename: Ángel I
authors.initials: ÁI
authors.lastname: Morales-Ramos
authors.forename: Yue H
authors.initials: YH
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Hilfiker
authors.forename: John S
authors.initials: JS
authors.lastname: Mecom
authors.forename: Patrick
authors.initials: P
authors.lastname: Eidam
authors.forename: Dongchuan
authors.initials: D
authors.lastname: Shi
authors.forename: Pei-San
authors.initials: PS
authors.lastname: Tseng
authors.forename: Carl
authors.initials: C
authors.lastname: Brooks
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Jon-Paul
authors.initials: JP
authors.lastname: Jaworski
authors.forename: Dwight
authors.initials: D
authors.lastname: Morrow
authors.forename: Harvey
authors.initials: H
authors.lastname: Fries
authors.forename: Richard
authors.initials: R
authors.lastname: Edwards
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D010080:Oxazoles; D011728:Pyridones; D058308:Receptors, Prostaglandin E, EP3 Subtype