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Published on: August 16, 2018
Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists
James S Scott1, Suzanne S Bowker, Katy J Brocklehurst
1Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
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.
Insights
Researchers developed a novel compound targeting G protein-coupled receptor 119 (GPR119) for metabolic syndrome. The new drug candidate avoids seizure side effects seen in earlier versions, demonstrating efficacy in mouse models.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Neuroscience
Background:
- G protein-coupled receptor 119 (GPR119) agonism is a promising therapeutic strategy for type II diabetes and metabolic syndrome.
- Early drug candidates exhibited dose-dependent tonic-clonic convulsions in mice, necessitating safety improvements.
Purpose of the Study:
- To develop a safer GPR119 agonist with reduced seizure liability.
- To optimize pharmacokinetic properties and in vivo efficacy for metabolic syndrome treatment.
Main Methods:
- In vitro hippocampal brain slice assay to evaluate seizure potential.
- Structure-activity relationship studies, replacing a 3-cyano pyridyl group with an aryl sulfone, then an alkyl sulfone.
- Pharmacokinetic profiling and in vivo efficacy testing in wild-type and GPR119 knockout mice.
Main Results:
- An aryl sulfone intermediate was identified to mitigate seizure liability.
- Alkyl sulfone 16 demonstrated no tonic-clonic convulsions in mice.
- Compound 16 exhibited favorable pharmacokinetics and in vivo efficacy.
- Efficacy was confirmed to be GPR119-dependent, as it was absent in GPR119 knockout mice.
Conclusions:
- Alkyl sulfone 16 represents a promising GPR119 agonist candidate for metabolic syndrome.
- The developed compound offers an improved safety profile compared to earlier candidates.
- This study validates GPR119 agonism as a therapeutic target for metabolic disorders.
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