Discovery of MKP10241, a Novel Small Molecule Targeting the GPR119/Incretin Axis to Treat Metabolic Disorders

GPR119 modulation is reported to have a promising role for preventing or managing various metabolic disorders, including type 2 diabetes, insulin resistance, loss of beta cell function, hyperlipidemia, obesity, fatty liver, MASH, and cirrhosis. We have developed a potent GPR119 agonist, MKP10241, which has elevated cyclic adenosine monophosphate (cAMP) levels in the GPR119 expressing cell line and reduced blood glucose levels and HbA1c in acute models and a chronic diabetic mouse model. Chronic treatment of MKP10241 in DIO-mice exhibited marked reduction in body weight and feed intake at tested doses, which was associated with decreased blood glucose level, lipid parameters, and body fats. Further evaluation of MKP10241 in the STAM mouse model of MASH/MASLD showed significant MASH resolution. MKP10241 was evaluated in preclinical toxicity and genotoxicity studies in rats and dogs and found safe. Considering the preclinical safety and efficacy profile, MKP10241 has been advanced for safety, tolerability, and pharmacokinetic evaluation in healthy volunteers in a Phase-I clinical trial.