Madhavan G R, Chakrabarti R, Kumar S K, Misra P, Mamidi R N, Balraju V, Kasiram K, Babu R K, Suresh J, Lohray B B, Lohrayb V B, Iqbal J, Rajagopalan R
Discovery Chemistry, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, 500 050, Hyderabad, India.
Eur J Med Chem. 2001 Jul-Aug;36(7-8):627-37. doi: 10.1016/s0223-5234(01)01257-0.
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.
我们在此报告一系列5-[4-[2-[取代酞嗪酮-2(或4)基]乙氧基]苯基甲基]噻唑烷-2,4-二酮和5-[4-[2-[2,3-苯并恶嗪-4-酮-2-基]乙氧基]苯基甲基]噻唑烷-2,4-二酮的合成及其在db/db小鼠体内降低血糖和甘油三酯的活性。在HEK 293T细胞中进行了体外PPARγ反式激活试验。体外和体内药理学研究表明，酞嗪酮类似物具有更好的活性。该系列中最佳化合物PHT46（化合物5a）在体外PPARγ反式激活潜力方面优于曲格列酮和吡格列酮。在胰岛素抵抗的db/db小鼠中，PHT46在降低血糖和甘油三酯方面的活性优于标准药物。Wistar大鼠的药代动力学研究表明PHT46具有良好的全身暴露性。Wistar大鼠的亚慢性毒性研究未显示任何与治疗相关的不良反应。
