Discovery of Novel GPR119 Agonists with Improved Kinetic Solubility and Drug-like Properties for Type 2 Diabetes Treatment
Jaeki Min, Jihun Kim, Kyeongwon Moon, Mincheol Kim, Dong-Hyeon Suh, Jaewon Lee, Moosung Ko, Jaeyoung Lee, Younghue Han, Inae Jang, Gyu Tae Park, Hyun-Mo Yang, Jeonghyun Min, Seungyeon Lee, Amitava Rakshit, Soo Bong Han, Pargat Singh, Changsik Lee, In Su KimAbstract
GPR119 is a compelling therapeutic target for type 2 diabetes due to its role in promoting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucose-dependent insulin secretion. This study aimed to develop a series of novel GPR119 agonists with exceptional kinetic solubility over a broad pH range featuring an N-alkyl piperidine head and pyrrolidine 2-carboxamide tail. Among the synthesized compounds, 18f demonstrated potent activity, exhibiting nanomolar potency (EC50 = 12.6 nM) in the hGPR119-cAMP functional assay as well as a 33.3% hypoglycemic effect in an oral glucose tolerance test. A significant enhancement (175.9%) of total GLP-1 levels was observed at 10 mg/kg administration of compound 18f. Further, compound 18f outperformed the antidiabetic effect of sitagliptin as the DPP-4 inhibitor in female Zucker Diabetic Fatty rats. Furthermore, the favorable pharmacokinetic profiles of compound 18f underscore its potential as a promising lead compound for type 2 diabetes treatment.