Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists

Maria-Jesus Blanco; Tatiana Vetman; Srinivasan Chandrasekhar; Matthew J Fisher; Anita Harvey; Daniel Mudra; Xu-Shan Wang; Xiao-Peng Yu; Matthew A Schiffler; Alan M Warshawsky

doi:10.1016/j.bmcl.2015.11.023

Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists

Bioorg Med Chem Lett. 2016 Jan 1;26(1):105-9. doi: 10.1016/j.bmcl.2015.11.023. Epub 2015 Nov 10.

Affiliations

¹ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: blanco_maria@lilly.com.
² Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.

PMID: 26608552
DOI: 10.1016/j.bmcl.2015.11.023

Abstract

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed.

Keywords: Arthritis pain; EP4 receptor antagonist; Human whole blood assay; Prostaglandin E2.

MeSH terms

Benzoates / chemical synthesis
Benzoates / chemistry
Benzoates / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Benzoates
Naphthalenes
Receptors, Prostaglandin E, EP4 Subtype