Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists

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• 作者：James S. Scott ; Suzanne S. Bowker ; Katy J. Brocklehurst ; Hayley S. Brown ; David S. Clarke ; Alison Easter ; Anne Ertan ; Kristin Goldberg ; Julian A. Hudson ; Stefan Kavanagh ; David Laber ; Andrew G. Leach ; Philip A. MacFaul ; Elizabeth A. Martin ; Darren McKerrecher ; Paul Schofield ; Per H. Svensson ; Joanne Teague
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：57
• 期：21
• 页码：8984-8998
• 全文大小：782K
• ISSN：1520-4804

文摘

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鈥揷lonic 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鈥揷lonic 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.