GLPG0974

Last updated

GLPG0974
GLPG0974 structure.png
Identifiers
  • 4-[[(2R)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C25H25ClN2O4S
Molar mass 485.00 g·mol−1
3D model (JSmol)
  • C[C@@]1(CCN1C(=O)C2=CSC3=CC=CC=C32)C(=O)N(CCCC(=O)O)CC4=CC(=CC=C4)Cl
  • InChI=1S/C21H21ClN2OS/c1-21(2,3)18(15-9-11-16(22)12-10-15)19(25)24-20-23-13-17(26-20)14-7-5-4-6-8-14/h4-13,18H,1-3H3,(H,23,24,25)/t18-/m0/s1
  • Key:MPMKMQHJHDHPBE-RUZDIDTESA-N

GLPG0974 is an experimental drug which acts as a reasonably potent and selective antagonist for the free fatty acid receptor FFAR2 (GPR43). It was originally developed as a potential medication for ulcerative colitis, and while it was not developed as a medicine for this application it has remained widely used as a pharmacological tool compound for research into the FFAR2 receptor, as one of the relatively few selective FFAR2 antagonists available. [1] [2] [3] [4] [5] Despite its antagonist action, it can also act as a positive allosteric modulator of FFAR2 under some conditions, which can complicate interpretation of results obtained using GLPG0974 in the presence of other FFAR2 ligands. [6]

References

  1. ↑ Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanqué R, et al. (December 2014). "Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic". Journal of Medicinal Chemistry. 57 (23): 10044–10057. doi:10.1021/jm5012885. PMID   25380412.
  2. ↑ Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, et al. (July 2016). "Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects". British Journal of Clinical Pharmacology. 82 (1): 139–148. doi:10.1111/bcp.12900. PMC   4917808 . PMID   26852904.
  3. ↑ Akiba Y, Maruta K, Narimatsu K, Said H, Kaji I, Kuri A, et al. (August 2017). "FFA2 activation combined with ulcerogenic COX inhibition induces duodenal mucosal injury via the 5-HT pathway in rats". American Journal of Physiology. Gastrointestinal and Liver Physiology. 313 (2): G117 –G128. doi:10.1152/ajpgi.00041.2017. PMC   5582879 . PMID   28526687.
  4. ↑ Miyasato S, Iwata K, Mura R, Nakamura S, Yanagida K, Shindou H, et al. (January 2023). "Constitutively active GPR43 is crucial for proper leukocyte differentiation". FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 37 (1): e22676. doi: 10.1096/fj.202201591R . PMID   36468834.
  5. ↑ Kugawa M, Kawakami K, Kise R, Suomivuori CM, Tsujimura M, Kobayashi K, et al. (March 2025). "Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2". Nature Communications. 16 (1) 2809. Bibcode:2025NatCo..16.2809K. doi:10.1038/s41467-025-57983-4. PMC   11947310 . PMID   40140663.
  6. ↑ Lind S, Hoffmann DO, Forsman H, Dahlgren C (February 2022). "Allosteric receptor modulation uncovers an FFA2R antagonist as a positive orthosteric modulator/agonist in disguise". Cellular Signalling. 90 110208. doi:10.1016/j.cellsig.2021.110208. PMID   34856356.
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