ABSTRACT
We report here the synthesis of a series of 5-[4-[2-[substituted phthalazinones-2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3-benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and their plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in this series, showed better in vitro PPARgamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showed better plasma glucose and triglyceride lowering activity than the standard drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatment-related adverse effect.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/pharmacology , Oxazines/pharmacology , Phthalazines/pharmacology , Receptors, Cytoplasmic and Nuclear/drug effects , Thiazolidinediones , Transcription Factors/drug effects , Triglycerides/antagonists & inhibitors , Animals , Cell Line/drug effects , Chromans/pharmacology , Disease Models, Animal , Female , Humans , Hypoglycemic Agents/therapeutic use , Hypolipidemic Agents/therapeutic use , Male , Mice , Mice, Inbred C57BL , Oxazines/chemistry , Phthalazines/chemistry , Pioglitazone , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Triglycerides/blood , TroglitazoneABSTRACT
A high-performance liquid chromatographic method for the determination of DRF-2189, using troglitazone as internal standard, is described. A dichloromethane-ethyl acetate solvent mixture (6:4, v/v) was used as the extraction solvent. A Kromasil C18 column with a mobile phase consisting of 0.05 M phosphate buffer-acetonitrile-methanol (22.5:37.5:40) (pH 5.0) was used at a flow-rate of 1.0 ml/min. The eluate was monitored by using fluorescence detection with excitation and emission wavelengths at 292 nm and 325 nm, respectively. Ratio of peak area of analyte to internal standard was used for quantification of plasma samples. Using this method, the absolute recovery of DRF-2189 from rat plasma was >95% and the limit of quantitation was 50 ng/ml. The intra-day relative standard deviation (R.S.D.) ranged from 1.74 to 7.24% at 1 microg/ml and 1.86 to 3.83% at 10 microg/ml. The inter-day R.S.D.s were 8.34 and 4.91% at 1 and 10 microg/ml, respectively. The method was applied to measure plasma concentrations of DRF-2189 in pharmacokinetic studies in Wistar rats.
