Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors

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• 作者：Rui Chen^a ; ^&dagger ; ; Jie Xiao^c ; ^&dagger ; ; Yong Ni^b ; Han-Fei Xu^b ; Min Zheng^b ; Xu Tong^a ; Tong-Tian Zhang^a ; Chenzhong Liao^b ; ^{czliao@hfut.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Wen-Jian Tang^a ; ^{ahmupharm@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：hMAO ; Isoform selectivity ; Benzoxazepinone ; Selective hMAO-B inhibitor ; Anti-Parkinson
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：24
• 期：8
• 页码：1741-1748
• 全文大小：1202 K

文摘

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.