Optimization of physicochemical properties of pyridone-based EP3 receptor antagonists

Xuqing Zhang; Bin Zhu; Lili Guo; Ivona Bakaj; Matthew Rankin; George Ho; Jack Kauffman; Seunghun P Lee; Lisa Norquay; Mark Macielag

doi:10.1016/j.bmcl.2021.128172

Optimization of physicochemical properties of pyridone-based EP3 receptor antagonists

Bioorg Med Chem Lett. 2021 Sep 1:47:128172. doi: 10.1016/j.bmcl.2021.128172. Epub 2021 Jun 6.

Authors

Affiliations

¹ Discovery Sciences, Discovery Chemistry, Janssen Research & Development, LLC, 1400 McKean Road, Box 776, Spring House, PA 19477, United States. Electronic address: xzhang@proteovanttx.com.
² Discovery Sciences, Discovery Chemistry, Janssen Research & Development, LLC, 1400 McKean Road, Box 776, Spring House, PA 19477, United States.
³ Cardiovascular and Metabolism Research, Janssen Research & Development, LLC, 1400 McKean Road, Box 776, Spring House, PA 19477, United States.
⁴ Discovery Sciences, Lead Discovery, Janssen Research & Development, LLC, 1400 McKean Road, Box 776, Spring House, PA 19477, United States.

PMID: 34091043
DOI: 10.1016/j.bmcl.2021.128172

Abstract

A novel series of pyridone-based EP3 receptor antagonists was optimized for good physical properties and oral bioavailability in rodents. The lead compounds 3h, 3l and 4d displayed good in vitro profiles, moderate to good metabolic stability and good rodent PK profiles with low clearance, high oral exposure and acceptable half-life.

Keywords: EP3; Metabolic stability; PGE2; Pyridone.

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Pyridones / chemistry
Pyridones / pharmacology*
Receptors, Prostaglandin E, EP3 Subtype / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Pyridones
Receptors, Prostaglandin E, EP3 Subtype