Article

Discovery of N-aryl-2-acylindole human glucagon receptor antagonists.

Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.65). 12/2011; 21(23):7124-30. DOI: 10.1016/j.bmcl.2011.09.105
Source: PubMed

ABSTRACT A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes.

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