GPR119 Agonists 2009–2011

Abstract

The increasing incidence of Type II diabetes mellitus worldwide continues to attract the attention and resources of the pharmaceutical industry in the pursuit of more effective therapies for blood glucose control. New approaches that compare favorably with classical medicaments while avoiding hypoglycemic episodes or waning effectiveness are paramount. Recent advances toward this end have been realized based on the biology of the glucagon like peptide-1 receptor (GLP1R). This β-cell-expressed GPCR has the ability to promote insulin release in a glucose-dependent fashion, and has been shown to elicit improved glycemic control and preservation of β-cell mass. Direct activation of GLP1R utilizing peptide mimetics has been achieved; however, attempts to access the biology of this receptor via small-molecule approaches have thus far been elusive. In this context, GPR119 has emerged as a tractable new alternative to GLP1R. GPR119 is another GPCR expressed on the β-cell, which, like GLP1R, signals in a glucose-dependent manner. Moreover, GPR119-mediated increases in GLP-1 and other incretins upon activation in the intestine further increase the insulinotropic activity of the β-cell. The early success in identifying small-molecule agonists of the GPR119 has prompted a rapid increase in the number of patent applications filed in the last few years. In this review we provide a comprehensive summary of all patent activity in this field that has appeared within the 2009-2011 timeframe.