Lactams as EP4 prostanoid receptor agonists. 3. Discovery of N-ethylbenzoic acid 2-pyrrolidinones as subtype selective agents.
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.
Elworthy
Todd R
TR
Roche Palo Alto, California 94304, USA. todd.elworthy@Roche.com
Brill
Emma R
ER
Chiou
San-San
SS
Chu
Frances
F
Harris
Jason R
JR
Hendricks
R Than
RT
Huang
Jane
J
Kim
Woongki
W
Lach
Leang K
LK
Mirzadegan
Tara
T
Yee
Calvin
C
Walker
Keith A M
KA
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
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