Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization.
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.
Elworthy
Todd R
TR
Roche Palo Alto, Department of Medicinal Chemistry, 3431Hillview Avenue, Palo Alto, CA 94304-1397, USA. todd.elworthy@roche.com
Kertesz
Denis J
DJ
Kim
Woongki
W
Roepel
Michael G
MG
Quattrocchio-Setti
Lina
L
Smith
David B
DB
Tracy
Jahari Laurant
JL
Chow
Audrey
A
Li
Fujun
F
Brill
Emma R
ER
Lach
Leang K
LK
McGee
Daren
D
Yang
Diana S
DS
Chiou
San-San
SS
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
D007769:Lactams; D011760:Pyrrolidinones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C028537:2-pyrrolidone