ABSTRACT
We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.
Subject(s)
Cyclohexanes/pharmacology , Hypoglycemic Agents/pharmacology , Oxadiazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Spiro Compounds/pharmacology , Animals , Cyclohexanes/chemical synthesis , Cyclohexanes/pharmacokinetics , Drug Stability , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Microsomes, Liver/metabolism , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Rats, Sprague-Dawley , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.
Subject(s)
Cyclohexanes/pharmacology , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Spiro Compounds/pharmacology , Animals , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Ligands , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50â¯=â¯4â¯nM) with no CYP inhibitory activity (IC50 >10⯵M). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.
