title: Lactams as EP4 prostanoid receptor agonists. 3. Discovery of N-ethylbenzoic acid 2-pyrrolidinones as subtype selective agents.
abstract: Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.
authors.affiliation: Roche Palo Alto, California 94304, USA. todd.elworthy@Roche.com
authors.forename: Todd R
authors.initials: TR
authors.lastname: Elworthy
authors.forename: Emma R
authors.initials: ER
authors.lastname: Brill
authors.forename: San-San
authors.initials: SS
authors.lastname: Chiou
authors.forename: Frances
authors.initials: F
authors.lastname: Chu
authors.forename: Jason R
authors.initials: JR
authors.lastname: Harris
authors.forename: R Than
authors.initials: RT
authors.lastname: Hendricks
authors.forename: Jane
authors.initials: J
authors.lastname: Huang
authors.forename: Woongki
authors.initials: W
authors.lastname: Kim
authors.forename: Leang K
authors.initials: LK
authors.lastname: Lach
authors.forename: Tara
authors.initials: T
authors.lastname: Mirzadegan
authors.forename: Calvin
authors.initials: C
authors.lastname: Yee
authors.forename: Keith A M
authors.initials: KA
authors.lastname: Walker
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D010084:Oxidation-Reduction; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013329:Structure-Activity Relationship
chemical_list: D001565:Benzoates; D001798:Blood Proteins; D007769:Lactams; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D011759:Pyrrolidines; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype