Design, synthesis, and effects of novel phenylpyrimidines as glucagon receptor antagonists

[Display omitted] •Design and synthesis of novel GCGR antagonists as pyrimidine derivatives.•The compound of (R)-7a decreased the glucagon-induced cAMP production.•The compound of (R)-7a decreased the glucagon-induced glucose production.•The compound of (R)-7a decreased the glucagon-induced glucose excursion in vivo.•The compound of (R)-7a lowering fasting blood glucose levels in db/db mice. The hormone glucagon increases blood glucose levels through increasing hepatic glucose output. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, the inhibition of glucagon receptor is one target for the treatment of hyperglycemia in type 2 diabetes. Here we designed and synthesized a series of small molecules based on phenylpyrimidine. Of these, the compound (R)-7a most significantly decreased the glucagon-induced cAMP production and glucagon-induced glucose production during in vitro and in vivo assays. In addition, (R)-7a showed good efficacy in glucagon challenge tests and lowered blood glucose levels in diabetic db/db mice. Our results suggest that the compound (R)-7a could be a potential glucose-lowering agent for treating type 2 diabetes.