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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 开发具有异构体选择性的一氧化氮合酶抑制剂仍然是该提案的中心焦点。基于在前两个建议期收集的结构信息，新一代nNOS选择性抑制剂被从头设计(参见。1)。通过体外抑制试验对新化合物进行筛选。那些被证明具有良好的效力和选择性的化合物随后被用于结构研究。在临床前动物实验中，也发现了最好的抑制剂对脑缺氧所致的脑性瘫痪有保护作用(参考文献2)。酶-抑制剂复合体结构是进一步修饰和改进新型抑制剂的关键。因此，我们希望将该提案再延长两年。

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.