DEVELOPMENT OF ISOFORM-SELECTIVE INHIBITORS OF NITRIC OXIDE SYNTHASES (NOS)

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 异构体选择性NOS抑制剂的发展仍然是这个建议的中心焦点。基于在前两个提案期间收集的结构信息，重新设计了新一代nNOS选择性抑制剂（参考文献1）。通过体外抑菌试验筛选新化合物。然后将显示具有良好效力和选择性的那些用于结构研究。在临床前动物试验中，还发现最好的抑制剂可预防脑缺氧引起的脑瘫（参考文献2）。 酶-抑制剂复合物的结构是进一步修饰和改进新型抑制剂的关键。因此，我们希望将该建议再延长两年。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Development of isoform selective NOS inhibitors continues to be the central focus of this proposal. Based on structural information gathered during the two previous proposal periods, a new generation of nNOS selective inhibitors were designed de novo (ref. 1). The new compounds were screened through in vitro inhibitory assays. Those shown to have good potency and selectivity were then used for structural studies. The best inhibitors were also found to protect against cerebral palsy induced by brain hypoxia in pre-clinical animal tests (ref.2). The enzyme-inhibitor complex structures are critical for further modification and improvement of new inhibitors. Therefore, we would like to extend the proposal for another two years.