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.

The use of small-molecule structures to complement protein–ligand crystal structures in drug discovery

“…In the generation of GPR119 agonists, scientists at AstraZeneca made probably the most elegant use of smallmolecule crystal structures to improve the solubility of their compounds yet published (Scott et al, 2012(Scott et al, , 2014. Noting that both 'ends' of their molecules self-associated in a symmetrygenerating manner, they replaced these groups with moieties which were bioisosteric but less self-complementary.…”

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

“…A possible CNS expression difference between human and rodent species is suggested in a patent application that indicates GPR119 is also expressed at high density in rat and mouse brain (Bonini et al, 2002 ). Mouse CNS expression is confirmed by high-affinity GPR119 binding and potent efficacy to reduce seizure-related hippocampal activity (Scott et al, 2014 ). At micromolar concentrations, the endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonist oleoylethanolamide (OEA) activates GPR119, while anandamide appears to have partial efficacy in yeast cells expressing the receptor (Overton et al, 2006 ).…”

Abstracts of the 25th International Isotope Society (UK Group) symposium: Synthesis and applications of labelled compounds 2016

“…Despite these advances, however, certain functionalities, which are ubiquitous throughout drug motifs, still present significant challenges for directed HIE. One particular example that has very limited application as a directing group is the sulfone . Indeed, previous attempts within the group to utilise this motif for directed HIE have proven unsuccessful …”