ABSTRACT
We previously reported the synthesis and biological activity of novel substituted pyridines and purines having thiazolidinedione with hypoglycemic and hypolipidemic activities. We now report the synthesis and antidiabetic activity of novel substituted pyrimidines having thiazolidinedione moiety. These compounds (entry No. 5a-i, 10a-d and 16) were evaluated for their glucose and lipid lowering activity in KKA(y) mice. From the results, novel compounds, 5c and 5g, exhibited considerably more potent biological activity than that of the reference compounds, pioglitazone and rosiglitazone, respectively.
Subject(s)
Drug Design , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Animals , Cell Line , Drug Evaluation, Preclinical , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/chemistry , Male , Mice , Mice, Mutant Strains , Models, Chemical , Pioglitazone , Pyrimidines/chemical synthesis , Rats , Rats, Sprague-Dawley , Rosiglitazone , Thiazolidinediones/chemical synthesisABSTRACT
A series of substituted pyridines and purines containing 2,4-thiazolidinedione were designed and synthesized from their corresponding pyridines and purines. These synthesized compounds (entry no. 6a-d, 12a-e, 18a-d, 23a-c) were evaluated for their effect on triglyceride accumulation in 3T3-L1 cells in vitro and their hypoglycemic and hypolipidemic activity in the genetically diabetic KKA(y) mice in vivo. On the basis of their biological activities, 5-(4-[2-[N-methyl-(5-phenyl-pyridin-2-yl)amino]ethoxy]benzyl)thiazolidine-2,4-dione (6d) was selected as a candidate for further pharmacological studies.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Purines/chemical synthesis , Purines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Thiazolidinediones/chemistry , 3T3-L1 Cells , Animals , Blood Glucose/drug effects , Cell Division/drug effects , Cells, Cultured , Disease Models, Animal , Drug Design , Hepatocytes/drug effects , Hepatocytes/metabolism , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/therapeutic use , Male , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley , Triglycerides/metabolismABSTRACT
A series of erythrose, ribose, and substituted pyrrolidine containing 2,4-thiazolidinediones were synthesized. Among them, thirteen unsaturated thiazolidinediones, six saturated thiazolidinediones and two unsaturated malonates were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. On the basis of the in vitro activity, 5-[4-[2-(1-benzyl-3,4-bis-benzyloxypyrrolidin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione 24b was selected as the candidate for further pharmacological studies.
