Synthesis of substituted 2H-benzo[e]indazole-9-carboxylate as a potent antihyperglycemic agent that may act through IRS-1, Akt and GSK-3β pathways12. Issue 2 (7th December 2016)

• Record Type: Journal Article
• Authors: Taneja, Gaurav; Gupta, Chandra Prakash; Mishra, Shachi; Srivastava, Rohit; Rahuja, Neha; Rawat, Arun Kumar; Pandey, Jyotsana; Gupta, Anand P.; Jaiswal, Natasha; Gayen, Jiaur R.; Tamrakar, Akhilesh K.; Srivastava, Arvind Kumar; Goel, Atul
• Is Part Of: MedChemComm. Volume 8:Issue 2(2017)
• Page Start: 329
• Page End: 337
• Publication Date: 2016-12-07
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c6md00467a
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : The synthesis and in vitro and in vivo antihyperglycemic activity of substituted 2 H -benzo[ e ]indazole-9-carboxylate are described. Abstract : Based on high throughput screening of our chemical library, we identified two 4, 5-dihydro-2 H -benzo[ e ]indazole derivatives (5d and5g ), which displayed a significant effect on glucose uptake in L6 skeletal muscle cells. Based on these lead molecules, a series of benzo[ e ]indazole derivatives were prepared. Among all the synthesized dihydro-2 H -benzo[ e ]indazoles, 8-(methylthio)-2-phenyl-6- p -tolyl-4, 5-dihydro-2 H -benzo[ e ]indazole-9-carboxylate (5e ) showed significant glucose uptake stimulation in L6 skeletal muscle cells, even better than lead compounds. Additionally, 5e decreased glucagon-induced glucose release in HepG2 hepatoma cells. The 2 H -benzo[ e ]indazole5e exerted an antihyperglycemic effect in normal, sucrose challenged streptozotocin-induced diabetic rats and type 2 diabetic db / db mice. Treatment with5e at a dose of 30 mg kg −1 in db / db mice caused a significant decrease in triglyceride and total cholesterol levels and increased the HDL-C level in a significant manner. The mechanistic studies revealed that the 2 H -benzo[ e ]indazole5e significantly stimulated insulin-induced signaling at the level of IRS-1, Akt and GSK-3β in L6 skeletal muscle cells, possibly by inhibiting protein tyrosine phosphatase-1B. This new 2 H -benzo[ e ]indazole derivative has potential for the treatment of diabetes with improved lipid profile.