Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction

Hayato Fukuda; Saki Ito; Kenji Watari; Chihiro Mogi; Mitsuhiro Arisawa; Fumikazu Okajima; Hitoshi Kurose; Satoshi Shuto

doi:10.1021/acsmedchemlett.6b00014

Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction

ACS Med Chem Lett. 2016 Feb 24;7(5):493-7. doi: 10.1021/acsmedchemlett.6b00014. eCollection 2016 May 12.

Authors

Hayato Fukuda¹, Saki Ito¹, Kenji Watari², Chihiro Mogi³, Mitsuhiro Arisawa¹, Fumikazu Okajima³, Hitoshi Kurose², Satoshi Shuto⁴

Affiliations

¹ Faculty of Pharmaceutical Science, Hokkaido University , Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, Japan.
² Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University , 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
³ Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University , 3-39-15 Showa-machi, Maebashi 371-8512, Japan.
⁴ Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, Japan.

Abstract

GPR4, a pH-sensing G protein-coupled receptor, is highly expressed in endothelial cells and may be activated in myocardial infarction due the decreased tissue pH. We are interested in GPR4 antagonists as potential effective pharmacologic tools and/or drug leads for the treatment of myocardial infarction. We investigated the structure-activity relationship of a known GPR4 antagonist 1 as a lead compound to identify 3b as the first potent and selective GPR4 antagonist, whose effectiveness was demonstrated in a mouse myocardial infarction model.

Keywords: GPR4; dibenzazepine derivatives; myocardial infarction; pH-sensing GPCR.