Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist

Yufang Xiao; Gian Luca Araldi; Zhong Zhao; Adulla Reddy; Srinivasa Karra; Nadia Brugger; David Fischer; Elizabeth Palmer; Bagna Bao; Sean D McKenna

doi:10.1016/j.bmcl.2007.11.020

Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist

Bioorg Med Chem Lett. 2008 Jan 15;18(2):821-4. doi: 10.1016/j.bmcl.2007.11.020. Epub 2007 Nov 13.

Authors

Yufang Xiao¹, Gian Luca Araldi, Zhong Zhao, Adulla Reddy, Srinivasa Karra, Nadia Brugger, David Fischer, Elizabeth Palmer, Bagna Bao, Sean D McKenna

Affiliation

¹ Department of Medicinal Chemistry, EMD-Serono Research Institute, Inc., Rockland, MA 02370, USA. yufang.xiao@emdserono.com

PMID: 18039575
DOI: 10.1016/j.bmcl.2007.11.020

Abstract

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.

MeSH terms

Animals
Female
Guinea Pigs
Humans
Lactams / chemical synthesis*
Lactams / pharmacokinetics
Lactams / pharmacology*
Male
Mice
Ovulation Induction
Receptors, Prostaglandin E / agonists*
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP4 Subtype
Structure-Activity Relationship

Substances

Lactams
PTGER2 protein, human
PTGER4 protein, human
Ptger2 protein, mouse
Ptger4 protein, mouse
Receptors, Prostaglandin E
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP4 Subtype