title: In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469.
abstract: Activation of the G protein-coupled free fatty acid receptor 1 (FFA1; formerly known as GPR40) leads to an enhancement of glucose-stimulated insulin secretion from pancreatic β-cells. TUG-469 has previously been reported as a potent FFA1 agonist. This study was performed to confirm the higher in vitro potency of TUG-469 compared to the reference FFA1 agonist GW9508 and to prove in vivo activity in a pre-diabetic mouse model. The in vitro pharmacology of TUG-469 was studied using Ca(2+)-, cAMP-, and impedance-based assays at recombinant FFA1 and free fatty acid receptor 4, formerly known as GPR120 (FFA4) expressing 1321N1 cells and the rat insulinoma cell line INS-1. Furthermore, we investigated the systemic effect of TUG-469 on glucose tolerance in pre-diabetic New Zealand obese (NZO) mice performing a glucose tolerance test after intraperitoneal administration of 5 mg/kg TUG-469. In comparison to GW9508, TUG-469 showed a 1.7- to 3.0-times higher potency in vitro at 1321N1 cells recombinantly expressing FFA1. Both compounds increased insulin secretion from rat insulinoma INS-1 cells. TUG-469 is > 200-fold selective for FFA1 over FFA4. Finally, a single dose of 5 mg/kg TUG-469 significantly improved glucose tolerance in pre-diabetic NZO mice. TUG-469 turned out as a promising candidate for further drug development of FFA1 agonists for treatment of type 2 diabetes mellitus.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Universitätsstr. 1, 40225, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Urban
authors.forename: A
authors.initials: A
authors.lastname: Hamacher
authors.forename: H J
authors.initials: HJ
authors.lastname: Partke
authors.forename: M
authors.initials: M
authors.lastname: Roden
authors.forename: S
authors.initials: S
authors.lastname: Schinner
authors.forename: E
authors.initials: E
authors.lastname: Christiansen
authors.forename: M E
authors.initials: ME
authors.lastname: Due-Hansen
authors.forename: T
authors.initials: T
authors.lastname: Ulven
authors.forename: H
authors.initials: H
authors.lastname: Gohlke
authors.forename: M U
authors.initials: MU
authors.lastname: Kassack
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D010666:Phenylpropionates / Q000494:pharmacology*; D011236:Prediabetic State / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000814:Aniline Compounds; D015415:Biomarkers; D001786:Blood Glucose; C473034:FFAR1 protein, human; C473036:Ffar1 protein, mouse; C515630:GW9508; D007004:Hypoglycemic Agents; D007328:Insulin; D008744:Methylamines; D010666:Phenylpropionates; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C000589451:TUG-469; D000242:Cyclic AMP