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Selective Novel Inverse Agonists for Human GPR43 Augment GLP-1 Secretion

Selective Novel Inverse Agonists for Human GPR43 Augment GLP-1 Secretion

Bi-Oh Park, Seong Heon Kim, Gye Yeong Kong, Da Hui Kim, Mi So Kwon, Su Ui Lee, Mun-Ock Kim, Sungchan Cho, Sangku Lee, Hyun-Jun Lee, Sang-Bae Han, Young Shin Kwak, Sung Bae Lee, Sunhong Kim

Eur J Pharmacol. 2016 Jan 15;771:1-9.

PMID: 26683635

Abstract:

GPR43/Free Fatty Acid Receptor 2 (FFAR2) is known to be activated by short-chain fatty acids and be coupled to Gi and Gq family of heterotrimeric G proteins. GPR43 is mainly expressed in neutrophils, adipocytes and enteroendocrine cells, implicated to be involved in inflammation, obesity and type 2 diabetes. However, several groups have reported the contradictory data about the physiological functions of GPR43, so that its roles in vivo remain unclear. Here, we demonstrate that a novel compound of pyrimidinecarboxamide class named as BTI-A-404 is a selective and potent competitive inverse agonist of human GPR43, but not the murine ortholog. Through structure-activity relationship (SAR), we also found active compound named as BTI-A-292. These regulators increased the cyclic AMP level and reduced acetate-induced cytoplasmic Ca(2+) level. Furthermore, we show that they modulated the downstream signaling pathways of GPR43, such as ERK, p38 MAPK, and NF-κB. It was surprising that two compounds augmented the secretion of glucagon-like peptide 1 (GLP-1) in NCI-H716 cell line. Collectively, these novel and specific competitive inhibitors regulate all aspects of GPR43 signaling and the results underscore the therapeutic potential of them.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1322598093	CATPB		1322598-09-3	Price
AP537679575	BTI-A-404		537679-57-5	Price

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