Discovery of 1,4-Disubstituted Cyclohexene Analogues as Selective GPR119 Agonists for the Treatment of Type 2 Diabetes

GPR119 has emerged as a promising target for treating type 2 diabetes and associated obesity, as its stimulation induces the secretion of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in the intestinal tract as well as the glucose-dependent release of insulin in pancreatic β-cells. We describe the design and synthesis of novel GPR119 agonists containing a 1,4-disubstituted cyclohexene scaffold. Compound 21b displayed nanomolar potency (EC₅₀ = 3.8 nM) for hGPR119 activation and demonstrated a hypoglycemic efficacy of 17.0% in an oral glucose tolerance test. The hypoglycemic effect of compound 21b, compared to sitagliptin, a DPP-4 inhibitor, showed the relatively higher efficacy in both FATZO and db/db mice. Additionally, compound 21b exhibited a significant reduction in body weight in a female diet-induced obese rat model, comparable to that of metformin. Furthermore, in vivo pharmacokinetic experiments revealed that compound 21b is a potential candidate for the treatment of type 2 diabetes and obesity.