Reddy K A, Lohray B B, Bhushan V, Bajji A C, Reddy K V, Reddy P R, Krishna T H, Rao I N, Jajoo H K, Rao N V, Chakrabarti R, Dileepkumar T, Rajagopalan R
Medicinal and Organic Chemistry, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India.
J Med Chem. 1999 Jun 3;42(11):1927-40. doi: 10.1021/jm980549x.
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.
合成了几种具有5-羟基-2,3-二氢-2,2,4,6,7-五甲基苯并呋喃部分及其5-苄氧基衍生物以及5-羟基-2,4,6,7-四甲基苯并呋喃部分的噻唑烷二酮衍生物，并在db/db小鼠中进行了评估。在噻唑烷二酮和取代苯并呋喃药效基团之间的连接基中插入一个N-甲基基团，其正常血糖活性有显著提高。当在结构中引入吡咯烷部分以得到5-[4-[N-[3(R/S)-5-苄氧基-2,3-二氢-2,2,4,6,7-五甲基苯并呋喃-3-基甲基]-(2S)-吡咯烷-2-基甲氧基]亚苯基]噻唑烷-2,4-二酮（21a）时，观察到了进一步的改善。以马来酸盐100 mg/kg/天的剂量给药时，化合物21a将血浆葡萄糖和甘油三酯降低到了瘦同窝小鼠的水平，即8±1 mM，是该系列中报道的最有效力和疗效的化合物。
