Based On The Estrogen Receptor And Peroxisome Proliferator Activated Receptor Drug Screening And Pharmacological Studies

Estrogen receptor (ER) is an important transcription factor affiliated to the nuclear receptor superfamily and plays key roles in reproductive, cardiovascular and central nervous systems and bone tissue. It has been a primary drug target for therapeutics directed against breast cancer, osteoporosis and some other diseases. In this thesis, a reporter gene based cellular assay was developed to study pharmacological properties of ER modulators. Among a series of compounds tested, Y134 was chosen for further studies both in vitro and in vivo.Briefly, cells were transiently tranfected with ER expression vector and a reporter gene and used to evaluate active compounds identified by a competitive radiolabeled ligand binding assay. While, raloxifene showed a weak agonist activity at a concentration of 10μM, its analogue Y134 only possesses a similar antagonist activity as oppose to raloxifene and is highly selective for ERα. This compund was further tested in ovariectomized mice and the results suggest that Y134 is a full ER antagonist in the breast and uterus and has a better selectivity for mammary gland than uterus in comparison with raloxifene. These data are useful in the development of new SERM for breast cancer treatment. Peroxisome proliferators activated receptorγ(PPARγ) is a member of the nuclear receptor superfamily. It possesses important physiological functions, and is associated with diabetes, atherosclerosis, inflammation, cancer, etc. Thiazolidinediones (TZDs) that target PPARγare widely used insulin sensitizers. Although TDZs can alleviate insulin resistance and are effective in treating type 2 diabetes, their side-effects such as weight gain and edema have caused great concerns. Therefore, discovery of novel PPARγagonists, with no or less adverse effects but retaining insulin-sensitizing property, is a focus for many pharmaceutical scientists.Following a high-throughput screening campaign. 12 compounds were identified to possess specific PPARγbinding properties. One such, namely, SH00012671 displayed a relatively high PPARγbinding feature (Ki=186.7 nM). Based on its structure, a series of new compounds were designed and synthesized. Using a cell-based reporter assay PPARγagonist activities of SH00012671 and its derivatives were evaluated in conjunction with adipose cell differentiation analysis. SH00012671 acted as an agonist in the reporter assay, but was unable to induce preadipocyte differentiation. However, the derivatives induced a significant level of preadipocyte differentiation, thereby providing a solid foundation for further medicinal chemistry improvements.