Novel tricyclic pyrazolo[1, 5-d][1, 4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Chen, Rui; Xiao, Jie; Ni, Yong; Xu, Han-Fei; Zheng, Min; Tong, Xu; Zhang, Tong-Tian; Liao, Chenzhong; Tang, Wen-Jian
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 8(2016)
• Page Start: 1741
• Page End: 1748
• Publication Date: 2016-04-15
• Subjects: hMAO -- Isoform selectivity -- Benzoxazepinone -- Selective hMAO-B inhibitor -- Anti-Parkinson; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.02.045
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Novel tricyclic pyrazolo[1, 5- d ][1, 4]benzoxazepin-5(6 H )-one as potential selective hMAO-B inhibitors were designed and synthesized. Modeling study indicated that the hMAO-B selectivity is determined by at least two residues, i.e., Ile 199 and Cys 172. Abstract: 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(6 H )-one were designed and synthesized. Compound3u (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.