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

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.