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.
Xiao
Yufang
Y
Department of Medicinal Chemistry, EMD-Serono Research Institute, Inc., Rockland, MA 02370, USA. yufang.xiao@emdserono.com
Araldi
Gian Luca
GL
Zhao
Zhong
Z
Reddy
Adulla
A
Karra
Srinivasa
S
Brugger
Nadia
N
Fischer
David
D
Palmer
Elizabeth
E
Bao
Bagna
B
McKenna
Sean D
SD
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