Discovery of the First Potent and Orally Efficacious Agonist of the Orphan G-Protein Coupled Receptor 119

Abstract

GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…In addition to exerting effects on insulin secretion, it was shown recently that oral administration of AR231453 to mice induced a rapid release of GLP-1 from intestinal L-cells [122]. This implies that GPR119 is also expressed by certain cells of the small intestine and this conclusion has received direct support by analysis of mRNA extracted from L-cells [123].…”

“…In an attempt to move forward the development of pharmacological ligands targeted to GPR119, a number of groups have reported the synthesis of small molecules which can serve as agonists of this receptor [114][115][116]. These have largely been developed on the basis of their ability to elicit a response in cells transfected to express GPR119 but, encouragingly, several have also been shown to display activity in vivo.…”

A lincRNA-DYNLRB2-2/GPR119/GLP-1R/ABCA1-dependent signal transduction pathway is essential for the regulation of cholesterol homeostasis

“…In addition, the GPR119-mediated release of GLP-1 from intestinal L-cells is protein kinase (PK)A dependent ( 10 ). Furthermore, cAMP, as a common second messenger that can activate MAPKs via PKA ( 11 ), can stimulate ABCA1 expression with species specifi c ( 12 ), alleviating the accumulation of cholesterol in macrophages by promoting ABCA1-mediated cellular cholesterol effl ux ( 13,14 ). Moreover, GPR119 can be activated by oleoylethanolamide and several other endogenous lipids containing oleic acid ( 15 ).…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…145 Optimization of 144 led to other GPR119 agonists. 146 In the field of T2DM, compound 145, a glucoside-based SGLT2 (sodium glucose co-transporter 2) inhibitor, entered development but was discontinued due to lack of sufficient stability in the gut and post-absorption.…”