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.
MeSH terms
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Animals
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Blood Glucose / drug effects*
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Cell Line / drug effects
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Chromans / pharmacology
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Diabetes Mellitus, Type 2 / drug therapy*
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Disease Models, Animal
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Female
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacology*
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Hypoglycemic Agents / therapeutic use
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / pharmacology*
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Hypolipidemic Agents / therapeutic use
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Male
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Mice
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Mice, Inbred C57BL
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Oxazines / chemistry
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Oxazines / pharmacology*
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Phthalazines / chemistry
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Phthalazines / pharmacology*
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Pioglitazone
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / drug effects*
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Structure-Activity Relationship
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Thiazolidinediones*
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Transcription Factors / drug effects*
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Triglycerides / antagonists & inhibitors*
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Triglycerides / blood
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Troglitazone
Substances
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Blood Glucose
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Chromans
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Hypoglycemic Agents
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Hypolipidemic Agents
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Oxazines
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Phthalazines
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Triglycerides
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2,4-thiazolidinedione
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Troglitazone
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Pioglitazone