Discovery and SAR of para-alkylthiophenoxyacetic acids as potent and selective PPARdelta agonists.

Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.

Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist.

Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound 4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes.

Novel phosphorus-containing 17beta-side chain mifepristone analogues as progesterone receptor antagonists.

A novel series of steroidal compounds were designed and synthesized with various phosphorus-containing groups on the 17beta-side chain as progesterone receptor antagonists. The structure-activity relationships of these compounds are discussed. Selected compounds were tested in an rat progesterone-sensitive assay. Some of these compounds are more potent than mifepristone, with a better selectivity profile in differentiating progesterone receptor from glucocorticoid receptor.

Alterations of myelin basic protein and ultrastructure in the limbic system at the early stage of trauma-related stress disorder in dogs.

BACKGROUND: The secondary injury and related complications after trauma are still the focus of trauma research. However, whether the remote effects on the central nervous system could be induced by high-energy missile extremity impact remains unclear. Also, the possible biomarker for brain damage in traumatic stress disorder has not been determined. METHODS: Forty-two healthy adult dogs were divided into three groups: the control group (n = 12), the high-speed trauma group (n = 15), and the low-speed trauma group (n = 15). Bilateral thighs of dogs were wounded with a smoothbore 6.2-mm rifle at a speed of 1,368 m/s (1.03-g steel bullet) for the high-speed trauma group and 625 m/s for the low-speed trauma group. The expression of myelin basic protein (MBP) in cerebrospinal fluid (CSF), hypothalamus and hippocampus of the limbic system, and temporoparietal cortex was investigated by enzyme-linked immunosorbent assay and dot-blot analysis. Also, the ultrastructure of the above areas was observed with light and electron microscopy. RESULTS: Neuronal degeneration and nerve fiber demyelination were seen in the hypothalamus and hippocampus in the high-speed trauma group at 8 hours after impact. The MBP level was markedly increased in the CSF (p < 0.01) in the two trauma groups, in the hypothalamus of the low-speed trauma group (p < 0.05), and in both the hypothalamus and the hippocampus of the high-speed trauma group (p < 0.01). The expression of MBP mRNA was also significantly enhanced in these areas at the same time. The increase of MBP content in the CSF was positively correlated with the elevation of MBP concentration in the hypothalamus and hippocampus. CONCLUSION: The hypothalamus and hippocampus of the limbic system in the central nervous system are vulnerable to damage after high-energy missile extremity impact, indicating that it might be one of the important pathologic bases involved in the development of trauma-related complications. Meanwhile, the MBP level in the CSF may be a sensitive biological indicator for brain damage at the early stage of trauma-related stress disorder.