ar-231453 and Diabetes-Mellitus--Type-2

The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.

Topics: Animals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.

Topics: Administration, Oral; Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Male; Mice; Rats, Sprague-Dawley; Rats, Zucker; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10mg/kg.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Discovery; Humans; Hypoglycemic Agents; Mice; Mice, Inbred C57BL; Molecular Structure; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled