Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists

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
QC 20200921
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.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
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

Bowker, Suzanne S.AstraZeneca, United Kingdom (author)
Brocklehurst, Katy J.AstraZeneca, United Kingdom (author)
Brown, Hayley S.AstraZeneca, United Kingdom (author)
Clarke, David S.AstraZeneca, United Kingdom (author)
Easter, AlisonAstraZeneca, United Kingdom; Stockholm University, Sweden (author)
Ertan, AnneAstraZeneca, Sweden (author)
Goldberg, KristinAstraZeneca, United Kingdom (author)
Hudson, Julian A.AstraZeneca, Sweden (author)
Kavanagh, Stefan L.AstraZeneca, United Kingdom (author)
Laber, DavidAstraZeneca, United Kingdom (author)
Leach, Andrew G.AstraZeneca, United Kingdom (author)
Macfaul, Philip A.AstraZeneca, United Kingdom (author)
Martin, Elizabeth A.AstraZeneca, United Kingdom (author)
McKerrecher, DarrenAstraZeneca, United Kingdom (author)
Schofield, PaulRISE,SP Process Development,AstraZeneca, United Kingdom; KTH Royal Institute of Technology, Sweden,Astra Zeneca (author)
Svensson, Per H.KTH,Kemi,AstraZeneca, Sweden(Swepub:kth)u1dgy3ip (author)
Teague, Joanne L.AstraZeneca, United Kingdom (author)
AstraZeneca, United KingdomAstraZeneca, United Kingdom; Stockholm University, Sweden (creator_code:org_t)

In:Journal of Medicinal Chemistry: American Chemical Society57:21, s. 8984-89980022-26231520-4804

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Neurology

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