title: Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists.
abstract: Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
authors.affiliation: Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Bowker
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Brocklehurst
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Brown
authors.forename: David S
authors.initials: DS
authors.lastname: Clarke
authors.forename: Alison
authors.initials: A
authors.lastname: Easter
authors.forename: Anne
authors.initials: A
authors.lastname: Ertan
authors.forename: Kristin
authors.initials: K
authors.lastname: Goldberg
authors.forename: Julian A
authors.initials: JA
authors.lastname: Hudson
authors.forename: Stefan
authors.initials: S
authors.lastname: Kavanagh
authors.forename: David
authors.initials: D
authors.lastname: Laber
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: Philip A
authors.initials: PA
authors.lastname: MacFaul
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Martin
authors.forename: Darren
authors.initials: D
authors.lastname: McKerrecher
authors.forename: Paul
authors.initials: P
authors.lastname: Schofield
authors.forename: Per H
authors.initials: PH
authors.lastname: Svensson
authors.forename: Joanne
authors.initials: J
authors.lastname: Teague
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004285:Dogs; D004830:Epilepsy, Tonic-Clonic / Q000517:prevention & control*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000595652:5-((2-fluoro-4-((methylsulfonyl)methyl)benzyl)oxy)-2-(2-methyl-4-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)pyrimidine; D051638:Ether-A-Go-Go Potassium Channels; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled