Open AccessDiscovery of a Novel Series of Pyridone-Based EP3 Antagonists for the Treatment of Type 2 Diabetes
Author(s) -
Xuqing Zhang,
Bin Zhu,
Lili Guo,
Ivona Bakaj,
Matthew M. Rankin,
George Ho,
Jack A. Kauffman,
Seunghun P. Lee,
Lisa D. Norquay,
Mark J. Macielag
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00667
Subject(s) - indazole , in vivo , pharmacology , bioavailability , in vitro , type 2 diabetes , chemistry , combinatorial chemistry , bioisostere , medicine , diabetes mellitus , biochemistry , stereochemistry , endocrinology , chemical synthesis , biology , microbiology and biotechnology
A novel series of pyridones were discovered as potent EP3 antagonists. Optimization guided by EP3 binding and functional assays as well as by eADME and PK profiling led to multiple compounds with good physical properties, excellent oral bioavailability, and a clean in vitro safety profile. Compound 13 was identified as a lead compound as evidenced by the reversal of sulprostone-induced suppression of glucose-stimulated insulin secretion in INS 1E β-cells in vitro and in a rat ivGTT model in vivo. A glutathione adduction liability was eliminated by replacing the naphthalene of structure 13 with the indazole ring of structure 43 .