Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist.
Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
Department of Medicinal Chemistry, EMD-Serono Research Institute, Inc., Rockland, MA 02370, USA. yufang.xiao@emdserono.com
Yufang
Y
Xiao
Gian Luca
GL
Araldi
Zhong
Z
Zhao
Adulla
A
Reddy
Srinivasa
S
Karra
Nadia
N
Brugger
David
D
Fischer
Elizabeth
E
Palmer
Bagna
B
Bao
Sean D
SD
McKenna
D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010062:Ovulation Induction; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013329:Structure-Activity Relationship
D007769:Lactams; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype