title: Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization.
abstract: A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.
authors.affiliation: Roche Palo Alto, Department of Medicinal Chemistry, 3431Hillview Avenue, Palo Alto, CA 94304-1397, USA. todd.elworthy@roche.com
authors.forename: Todd R
authors.initials: TR
authors.lastname: Elworthy
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Kertesz
authors.forename: Woongki
authors.initials: W
authors.lastname: Kim
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roepel
authors.forename: Lina
authors.initials: L
authors.lastname: Quattrocchio-Setti
authors.forename: David B
authors.initials: DB
authors.lastname: Smith
authors.forename: Jahari Laurant
authors.initials: JL
authors.lastname: Tracy
authors.forename: Audrey
authors.initials: A
authors.lastname: Chow
authors.forename: Fujun
authors.initials: F
authors.lastname: Li
authors.forename: Emma R
authors.initials: ER
authors.lastname: Brill
authors.forename: Leang K
authors.initials: LK
authors.lastname: Lach
authors.forename: Daren
authors.initials: D
authors.lastname: McGee
authors.forename: Diana S
authors.initials: DS
authors.lastname: Yang
authors.forename: San-San
authors.initials: SS
authors.lastname: Chiou
mesh_terms: D007769:Lactams / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011760:Pyrrolidinones / Q000737:chemistry* / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013237:Stereoisomerism
chemical_list: D007769:Lactams; D011760:Pyrrolidinones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C028537:2-pyrrolidone