A survey of small molecule glucagon receptor antagonists from recent patents (2006 - 2010)

The ever increasing prevalence of type 2 diabetes mellitus (T2DM) in the developed and developing nations calls for the introduction of new and more effective treatments. Glucagon receptor (GCGR) antagonists are highly validated in preclinical models of T2DM and thus have the potential to be developed as a new therapy. Small molecule GCGR antagonists have been an active area of research since the 1990s. As evidenced from the number of patents and laboratories involved, these efforts have accelerated during the last decade.

During the period 2006 - 2010, there were numerous patent publications from several laboratories claiming the discovery of novel small molecule GCGR antagonists. Herein, we present our interpretation of these new patent publications as well as follow-up disclosures appearing in the peer-reviewed literature. This paper provides an up-to-date overview of the field of small molecule GCGR antagonism as a potential treatment for T2DM. Attempts were made wherever possible to identify preferred or representative compounds from the patent applications reviewed. In vitro and in vivo data are also discussed where they were disclosed.

The novel small molecule GCGR antagonists reviewed here represent many diverse structural motifs. Some molecules are very potent antagonists of the GCGR in in vitro assays with acceptable selectivity. Some have intriguing in vivo activity in models of T2DM in a variety of preclinical species. It is to be hoped that clinical developments following these preclinical discoveries might result in a long-awaited new treatment for T2DM.