Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain

Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (±)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.

STUDIES ON XYLANASE PRODUCTION BY ASPERGILLUS CLAVATUS 22 / 微生物学通报

A high xylanase producing strain 22 of Aspergillus clavatus was screened from 105 strains of molds and yeasts. The suitable medium consisted of (g/L): bagasse hemicellulose 30, NH_4NO_3 5, yeast extract 5, wheat bran 10, Tween 80 1 and a small quantity of other minerals; initial pH 5.5. Theoptimalsporeinoculumwas4.9X10~6spores/ml (final concentration). Theactivity of xylanase was as high as 335.9 U/ml in shake-flask experiment at 28℃ for 72 h. The optimal temperature and pH for xylanase reaction were 50℃ and pH 4.8. 72.6% of its original activity was remained after incubation at 50℃ for 1 h, and 90% of the enzym activity was observed upon storage at 8℃ for 9 days . Sugars. Na~+. Ca~(2+). and Zn~(2+) increased its activity wherease Co~(2+)and Cu~(2+) inhibited it.

THE COMPARISON ON METHODS FOR ISOLATION OF NITRITE OXIDIZERS / 微生物学通报

Three methods for isolation of nitrite oxidizers-dilution method, silica-gel plate method and enrichment culture-capillary pipette method were compared. Among them the dilution method was most feasible and efficient.