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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

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

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