Small molecule glucagon receptor antagonists: an updated patent review (2015-2019).

INTRODUCTION: The peptide hormone glucagon acts as a counterregulatory response to hypoglycemia and as a key driver in the development of all forms of diabetes. Thus, inhibition of glucagon action, including through antagonism of the glucagon receptor by small molecule therapeutics, has been explored in clinical settings as a means to achieve glycemic control in patients with type 2 diabetes mellitus and mitigate associated comorbidities. AREAS COVERED: This review covers patent applications concerning small molecule glucagon receptor antagonists (GRAs) published between 2015 and 2019. With the exception of the cholesterol absorption inhibitor-GRA combination, patents, or applications pertaining to combination therapies or method of treatment were excluded. In addition, a discussion on findings from clinical trials is included. EXPERT OPINION: An evident trend toward declining discovery efforts in GRAs was observed. With respect to the structural novelty, most applications contain compounds broadly similar to earlier chemical matter. Based on findings from clinical trials, while GRAs are highly effective in lowering hemoglobin A1c (HbA1c) levels, key safety issues (cholesterol elevation, aminotransferase elevation, blood pressure effects) remain the primary hurdle for the field.