title: Discovery, optimisation and in vivo evaluation of novel GPR119 agonists.
abstract: GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.
authors: Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors: Katy J
authors: KJ
authors: Brocklehurst
authors: Anders
authors: A
authors: Broo
authors: Roger J
authors: RJ
authors: Butlin
authors: Hayley S
authors: HS
authors: Brown
authors: David S
authors: DS
authors: Clarke
authors: Öjvind
authors: Ö
authors: Davidsson
authors: Kristin
authors: K
authors: Goldberg
authors: Sam D
authors: SD
authors: Groombridge
authors: Elizabeth E
authors: EE
authors: Kelly
authors: Andrew
authors: A
authors: Leach
authors: Darren
authors: D
authors: McKerrecher
authors: Charles
authors: C
authors: O'Donnell
authors: Simon
authors: S
authors: Poucher
authors: Paul
authors: P
authors: Schofield
authors: James S
authors: JS
authors: Scott
authors: Joanne
authors: J
authors: Teague
authors: Leanne
authors: L
authors: Westgate
authors: Matt J M
authors: MJ
authors: Wood
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; C000606913:KCNH2 protein, human; D043562:Receptors, G-Protein-Coupled