Fxr Antagonist Design, Synthesis And Pharmacological Activities Of 4 - Methyl Substituted Pyrazole Research And Study On The Method Of Flavone Derivatives

The dissertation contains two chapters.Chapter 1 regards the design, synthesis and biological evaluation of FXR angtagonists. FXR is a member of Orphan nuclear receptor family, also a kind of ligand activation transcription factor. The recent research implies that as a bile acid agonist nuclear receptor, FXR participated in plenty of physiological processes in vivo. It highly relates to many metabolic syndrome including insulin resistance, impaired glucose tolerance, typeâ…¡diabetes, obesity, hyperlipidemia, hypertension, also played a important role in the occur and development of atherosclerosis. In the previous researches, we discovered a new kind of 4-benzylidene pyrozonlone-contanining FXR antagonist (A2). For illustrating the structure-activity relationships of A2 derivatives, totally, thirty-three 4-benzylidene pyrozonlone-contanining compounds were designed, synthesized (A1, B1-24, C1-2, D1-3, E1-2 and F1), and assayed against FXR based on homogeneous time-resolved fluorescence techniques. The results indicated that A2 derivatives are optionally as FXR antagonists, six compounds (B12, B14, B22, B24, C1 and C2) showed FXR antagonistic activities aroundμM (IC50=3.31-31.68μM), and two compounds (C1 and C2) showed potent FXR antagonistic activities around single digitμM (IC50=3.31μMå'Œ3.38μM). On the basis of biological results, we can deduce the preliminary structure-activity relationships (SARs) of these 34 compounds, which give some valuable clues for further design of FXR antagonists. The discovery has provided innovative thinking and novel structures for the research & development of anti-hypercholesterolemia drugs.Chapter 2 concerns the research on microwave-assisted one-pot synthesis of 4-arylidene-pyrazolone derivatives under solvent-free conditions.4-Arylidene-pyrazolone derivatives are an important class of heterocyclic compounds that occur in many drugs and active products. These compounds exhibit remarkable antitubercular, antifungal, antibacterial, anti-inflammatory, and antitumor activities. In our effort to identify new farnesoid X receptor (FXR) ligands, we recently found by virtual screening that a 4-arylidene-pyrazolone derivative A2 was a FXR antagonist. Consequently, to explore the structure activity relationships (SAR) for this family of compounds, a facile and practical approach for synthesizing 4-arylidenepyrazolone-containing derivatives became desirable. We have developed a simple, rapid, and efficient one-pot protocol for the preparation of the 4-arylidenepyrazolone derivatives by a solvent-free, microwave-assisted reaction. Furthermore, the procedure used commercially available reagents, giving the desired compounds in good to excellent yields (51-98%). The versatility of this methodology makes it suitable for library synthesis in drug discovery efforts, also helped us in completing the FXR antagonists molecular library construction.