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Glucagon antagonists for the treatment of Type 2 diabetes

1999; Taylor & Francis; Volume: 9; Issue: 6 Linguagem: Inglês

10.1517/13543776.9.6.701

1744-7674

Richard D. Connell,

Computational Drug Discovery Methods

AbstractInsulin and glucagon are the primary agents responsible for ensuring acute and long-term maintenance of glucose levels in the blood. There is strong evidence that excessive glucagon levels contribute to the hyperglycaemia of non-insulin dependent diabetes mellitus (NIDDM) by inappropriately stimulating hepatic glucose output in both fasting and fed states. The blocking of glucagon binding to its receptor was therefore considered a novel approach to reducing plasma glucose levels. Early efforts to prepare glucagon antagonists focused on peptidic analogues of glucagon. More recently, a number of small molecule glucagon antagonists have been reported which were obtained through high-throughput screening (HTS) of small molecule libraries. The historical work involving peptidic antagonists is reviewed first, followed by a review of the more recent developments with non-peptidic antagonists. The first small molecule antagonist from Bayer has just entered clinical trials. It is anticipated that this and future clinical trials will provide the first indications of the potential held by this new approach to disease management in diabetes.Keywordsdiabetesdiabetes mellitusglucagon analogueG-protein coupled receptorglucagon antagonistglucagon receptor antagonistsnon-insulin dependent diabetes mellitusType 1 diabetesType 2 diabetes