Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control.

We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.

Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.

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.