Synthesis and evaluation of fibrates for anti-diabetic and lipid lowering activity

Abhishekkashyap., Nargund. L.V.G and Shantaram. U

Low circulating levels HDLC and high circulating levels of TG levels constitutes a major risk factor for cardiovascular disease: These are also frequently observed among patients with type II Diabetes mellitus (DM). The principal hypolipidimic agents currently in use majorly are fibrates, a PPAR α agonist. Among oral hypoglycemic agents thiazolidinedione, PPAR γ agonist, effective in reducing elevated blood sugar levels. In the present study we are reporting a systematic synthesis of fibrate analogues PPAR α agonists and a PPAR α-γ dual agonist. Synthesis of PPAR α-γ dual agonist is done by hybridisation approach by combining of lead molecules of both class of drugs namely, fibrate and Thiazolidinedione for dual agonist activity (PPAR α-γ). A series of fibrate analogues is synthesized by forming a scaffold(26) in scheme6. A series of ten derivatives (28a to 28j) is synthesized by reacting scaffold (26) and different amines. PPAR α-γ dual agonist is synthesized by merging pharmacophores of fibrate and thiazolidinedione. In scheme-7; 2, 4 thiazolidinedione is synthesized and scaffold (32) is synthesized from 2, 4 thiazolidinedione. Further in scheme-7 compound (33) is synthesized form scaffold 32. Compounds 28e and 33 are undertaken for blood TG lowering effect and blood glucose lowering effect by using respective Preicugent commercial assay kits. Screening was undertaken for blood triglyceride lowering effect and blood glucose lowering effect for 28e and 33.

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