GPR119 agonists for the treatment of type 2 diabetes: an updated patent review (2014-present)

ABSTRACT

Introduction: Type 2 diabetes is a rapid-growing complex chronic metabolic disease characterized by hyperglycemia due to lessened insulin secretion, insulin resistance and hepatic glucose overproduction. GPR119 is a class A of G protein-coupled receptor, expressed on certain enteroendocrine L and K cells in the small intestine and by β-cells within the islets of Langerhans of the pancreas. Activation of GPR119 stimulates the secretion of glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose-dependent release of insulin in pancreatic β-cells.

Area covered: This review summarized the reported patents on GPR119 agonists from 2014 to present. The authors described the structural features of these novel synthetic molecules and compared their biological activities (including in vitro and in vivo) as potent GPR119 agonists for the treatment of diabetes.

Expert opinion: GPR119 agonists remain the advantage of stimulating both insulin and incretin release in a glucose-dependent manner over other hypoglycemic agents, although some GPR119 agonist clinical candidates have been discontinued in Phase І or Phase II. GPR119 agonists will succeed to be developed as anti-diabetic drugs after accumulated scaffolds of agonists are discovered and the crystallographic structure of GPR119 is elucidated. The synergic effect of GPR119 agonist and DPP-4 inhibitor will also elicit a benefit for the new therapeutic of diabetes.

KEYWORDS:

• Diabetes
• GLP-1
• GPR119
• scaffolds
• synthetic agonists

Article highlights

• GPR119 has been considered as a promising antidiabetic target.

• This review summarized the structural feature and bioactivity of synthetic GPR119 agonists reported in the patents from 2014 to present.

• The patented compounds were classified by a variety of scaffolds.

• Most compounds showed nanomolar activation of GPR119.

• The synergic effect of GPR119 agonist and DPP-4 inhibitor is beneficial for development of novel hypoglycaemic drugs based on the GLP-1 related mechanism.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by Jiangxi Provincial Department of Science and Technology (20192ACB21012) and the Education Department of Jiangxi Province (GJJ201211).