Pharmacological properties of acid N-thiazolylamide FFA2 agonists

Pharmacology Research and Perspectives

Volumn 3, Issue 3, 2015, Pages

  Brown, Andrew J ^a   Tsoulou, Christina ^a   Ward, Emma ^a   Gower, Elaine ^a   Bhudia, Nisha ^a   Chowdhury, Forhad ^a   Dean, Tony W ^a   Faucher, Nicolas ^b   Gangar, Akanksha ^b   Dowell, Simon J ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

^b GLAXOSMITHKLINE   (France)

Author keywords

4 CMTB; allosteric agonist; FFA2; GPR43; lipolysis; N thiazolylamide

Indexed keywords

4 CHLORO ALPHA (1 METHYLETHYL) N 2 THIAZOLYL BENZENEACETAMIDE; BENZENEACETAMIDE DERIVATIVE; CYCLIC AMP; FATTY ACID; GLUCAGON LIKE PEPTIDE 1; UNCLASSIFIED DRUG;

ADIPOCYTE; ALLOSTERISM; ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CALCIUM BLOOD LEVEL; CALCIUM MOBILIZATION; CELL DIFFERENTIATION; EPIDIDYMIS FAT; EXPLANT; HUMAN; HUMAN CELL; IC50; LIPOLYSIS; MALE; MOUSE; NONHUMAN; NORMAL HUMAN; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL;

EID: 84979465774     PISSN: None     EISSN: 20521707     Source Type: Journal    
DOI: 10.1002/prp2.141     Document Type: Article

References (32)

1. Bertheleme N, Singh S, Dowell SJ, Hubbard J, Byrne B (2013). Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor. Br J Pharmacol 169: 988–998.
2. Bill A (1990)Method and means for inducing, resp., preventing constriction of the pupil in the eye. Patent WO1990011773A1.
3. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, et al. (2003). The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278: 11303–11311.
4. Brown AJ, Dyos SL, Whiteway MS, White JHM, Watson M-A, Marzioch M, et al. (2000). Functional coupling of mammalian receptors to the yeast mating pathway using novel yeast/mammalian G protein α-subunit chimeras. Yeast 16: 11–22.
5. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al. (2003). The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278: 11312–11319.
6. Brown AJ, Daniels DA, Kassim M, Brown S, Haslam CP, Terrell VR, et al. (2011). Pharmacology of GPR55 in yeast and identification of GSK494581A as a mixed-activity glycine transporter subtype 1 inhibitor and GPR55 agonist. J Pharmacol Exp Ther 337: 236–246.
7. Covington DK, Briscoe CA, Brown AJ, Jayawickreme CK (2006). The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing. Biochem Soc Trans 34: 770–773.
8. Dewulf EM, Ge Q, Bindels LB, Sohet FM, Cani PD, Brichard SM, et al. (2013). Evaluation of the relationship between GPR43 and adiposity in human. Nutr Metab (Lond) 10: 11. doi: 10.1186/1743-7075-10-11
9. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, et al. (2005). Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11: 90–94.
10. Hoyveda H, Brantis CE, Dutheuil G, Zoute L, Schils D, Bernard J (2010) Compounds, pharmaceutical composition and methods for use in treating metabolic disorders. Patent WO2010066682.
11. Hudson BD, Tikhonova IG, Pandey SK, Ulven T, Milligan G (2012). Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3. J Biol Chem 287: 41195–41209.
12. Hudson BD, Due-Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, et al. (2013a). Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem 288: 17296–17312.
13. Hudson BD, Ulven T, Milligan G (2013b). The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs. Curr Top Med Chem 13: 14–25.
14. Kenakin T (2001). Inverse, protean, and ligand-selective agonism: matters of receptor conformation. FASEB J 15: 598–611.
15. Kenakin TP (2009). Allosteric drug antagonism. Pp. 129–146in ???. ????, ed.A pharmacology primer: theory, applications and methods. Elsevier, Burlington, MA.
16. Lane JR, Sexton PM, Christopoulos A (2013). Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol Sci 34: 59–66.
17. Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, et al. (2014). A new mechanism of allostery in a G protein-coupled receptor dimer. Nat Chem Biol 10: 745–752.
18. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, et al. (2008). Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol 74: 1599–1609.
19. Lin DC, Guo Q, Luo J, Zhang J, Nguyen K, Chen M, et al. (2012). Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol 82: 843–859.
20. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. (2009). Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282–1286.
21. Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanque R, et al. (2014). Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. J Med Chem 57: 10044–10057.
22. Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F, et al. (2009). G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183: 7514–7522.
23. Slack RJ, Hall DA (2012). Development of operational models of receptor activation including constitutive receptor activity and their use to determine the efficacy of the chemokine CCL17 at the CC chemokine receptor CCR4. Br J Pharmacol 166: 1774–1792.
24. Smith NJ, Ward RJ, Stoddart LA, Hudson BD, Kostenis E, Ulven T, et al. (2011). Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol Pharmacol 80: 163–173.
25. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, et al. (2013). Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen 18: 599–609.
26. Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, et al. (2014). High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513: 124–127.
27. Stoddart LA, Smith NJ, Jenkins L, Brown AJ, Milligan G (2008). Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J Biol Chem 283: 32913–32924.
28. Tang C, Ahmed K, Gille A, Lu S, Grone HJ, Tunaru S, et al. (2015). Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 21: 173–177.
29. Ulven T (2012). Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne) 3: 111.
30. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly Y, et al. (2011). SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One 6: e21205.
31. Wang J, Wu X, Simonavicius N, Tian H, Ling L (2006). Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem 281: 34457–34464.
32. Wang Y, Jiao X, Kayser F, Liu J, Wang Z, Wanska M, et al. (2010). The first synthetic agonists of FFA2: discovery and SAR of phenylacetamides as allosteric modulators. Bioorg Med Chem Lett 20: 493–498.