Chen Rui, Xiao Jie, Ni Yong, Xu Han-Fei, Zheng Min, Tong Xu, Zhang Tong-Tian, Liao Chenzhong, Tang Wen-Jian
School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, PR China.
Bioorg Med Chem. 2016 Apr 15;24(8):1741-8. doi: 10.1016/j.bmc.2016.02.045. Epub 2016 Mar 3.
Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a-3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50=221 nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50=321 nM), which is a commercial selective hMAO-B inhibitor used to Parkinson's disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors.
基于我们最近报道的选择性人源单胺氧化酶A（hMAO-A）抑制剂，在其基础上，分子内环化导致了同工型选择性的非常有趣的变化。设计并合成了一系列具有新型三环吡唑并[1,5-d][1,4]苯并恶唑嗪-5(6H)-酮骨架的选择性人源单胺氧化酶B（hMAO-B）抑制剂（3a - 3u）。化合物3u（IC50 = 221 nM）对hMAO-B表现出最佳的抑制活性和同工型选择性，优于司来吉兰（IC50 = 321 nM），司来吉兰是一种用于治疗帕金森病的商业选择性hMAO-B抑制剂。模型研究表明，我们的化合物对hMAO-B的选择性至少由两个残基决定，即Ile 199和Cys 172（或hMAO-A中对应的Phe 208和Asn 181）。这些数据支持进一步研究以评估更高效选择性hMAO-B抑制剂的合理设计。
