Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonistsShow others and affiliations
2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 21, p. 8984-8998Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
American Chemical Society , 2014. Vol. 57, no 21, p. 8984-8998
Keywords [en]
5 ({2 fluoro 4 [(methylsulfonyl)methyl]benzyl}oxy) 2 {(2r) 2methyl 4 [3 (trifluoromethyl) 1, 2, 4 oxadiazol 5 yl]piperazin 1 yl} pyrimidine, alkyl group, anticonvulsive agent, G protein coupled receptor, g protein coupled receptor 119, potassium channel HERG, sitagliptin, sulfone, unclassified drug, 5-((2-fluoro-4-((methylsulfonyl)methyl)benzyl)oxy)-2-(2-methyl-4-(3-(trifluoromethyl)-1, 2, 4-oxadiazol-5-yl)piperazin-1-yl)pyrimidine, antidiabetic agent, Gpr119 protein, mouse, oxadiazole derivative, pyrimidine derivative, animal cell, animal experiment, animal model, area under the curve, Article, brain slice, clinical study, controlled study, crystal structure, dose response, drug blood level, drug efficacy, drug structure, female, hippocampus, in vitro study, in vivo study, male, maximum plasma concentration, mouse, nonhuman, tonic clonic seizure, volume of distribution, wild type, agonists, animal, C57BL mouse, chemistry, Diabetes Mellitus, Type 2, dog, drug effects, Epilepsy, Tonic-Clonic, knockout mouse, structure activity relation, Animals, Dogs, Ether-A-Go-Go Potassium Channels, Hypoglycemic Agents, Mice, Inbred C57BL, Mice, Knockout, Oxadiazoles, Pyrimidines, Receptors, G-Protein-Coupled, Structure-Activity Relationship
National Category
Engineering and Technology
Identifiers
URN: urn:nbn:se:ri:diva-45529DOI: 10.1021/jm5011012Scopus ID: 2-s2.0-84923767827OAI: oai:DiVA.org:ri-45529DiVA, id: diva2:1457112
Note
CODEN: JMCMA; Correspondence Address: Scott, J.S.; Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, United Kingdom; email: jamie.scott@astrazeneca.com; Chemicals/CAS: sitagliptin, 486460-32-6, 654671-78-0, 654671-77-9; sulfone, 67015-63-8; 5-((2-fluoro-4-((methylsulfonyl)methyl)benzyl)oxy)-2-(2-methyl-4-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)pyrimidine; Ether-A-Go-Go Potassium Channels; Gpr119 protein, mouse; Hypoglycemic Agents; Oxadiazoles; Pyrimidines; Receptors, G-Protein-Coupled
2020-08-102020-08-102021-06-16Bibliographically approved