Design and synthesis of conformationally constrained tri-substituted ureas as potent antagonists of the human glucagon receptor

A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Compound 4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as 3 mg/kg.

Graphical abstractA series of conformationally constrained tri-substituted ureas (arrow indicates the position for conformation constraint in the Figure) were synthesized and their potential as the human glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice which contain a humanized glucagon receptor. Compound 4a was also efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at doses as low as 3 mg/kg.Figure optionsDownload full-size imageDownload as PowerPoint slide