title: Selective novel inverse agonists for human GPR43 augment GLP-1 secretion.
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.
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Bi-Oh
authors.initials: BO
authors.lastname: Park
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Gye Yeong
authors.initials: GY
authors.lastname: Kong
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Da Hui
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Daejeon, Republic of Korea.
authors.forename: Mi So
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea.
authors.forename: Su Ui
authors.initials: SU
authors.lastname: Lee
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea.
authors.forename: Mun-Ock
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Sungchan
authors.initials: S
authors.lastname: Cho
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea.
authors.forename: Sangku
authors.initials: S
authors.lastname: Lee
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea.
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy, Korea University, Sejong, Republic of Korea.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Kwak
authors.affiliation: Department of Brain Science, DGIST, Daegu, Republic of Korea. Electronic address: sblee@dgist.ac.kr.
authors.forename: Sung Bae
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Incurable Disease Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea. Electronic address: sunhong@kribb.re.kr.
authors.forename: Sunhong
authors.initials: S
authors.lastname: Kim
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D011744:Pyrimidinones / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled
chemical_list: D000814:Aniline Compounds; D002118:Calcium; D000242:Cyclic AMP; D052216:Glucagon-Like Peptide 1; D011744:Pyrimidinones; D011956:Receptors, Cell Surface; C000611676:BTI-A-404; C473103:FFAR2 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Acetate (Pubchem CID:176); BTI-A-202; BTI-A-404; CATPB (Pubchem CID:53308747); GLP-1; GPR43; Inverse agonist; Propionate (Pubchem CID:1032); SCFA