Lactams as prostanoid receptor ligands. Part 4: 2-Piperidones as selective EP4 receptor agonists.
2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be 95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4 prostanoid receptor. They displayed a high affinity (Ki 5-130 nM) at EP4 and subtype selectivity.
Elworthy
Todd R
TR
Roche Palo Alto, Department of Medicinal Chemistry, 3431 Hillview Avenue, Palo Alto, CA 94304-1397, USA. todd.elworthy@roche.com
Brill
Emma R
ER
Caires
Christopher C
CC
Kim
Woongki
W
Lach
Leang K
LK
Tracy
Jahari Laurant
JL
Chiou
San-San
SS
D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype
D007769:Lactams; D008024:Ligands; D010881:Piperidones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype