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

Publication date: Available online 3 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Rui Chen, Jie Xiao, Yong Ni, Han-Fei Xu, Min Zheng, Xu Tong, Tong-Tian Zhang, Chenzhong Liao, Wen-Jian Tang
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.

Graphical abstract

from #Medicine via ola Kala on Inoreader http://ift.tt/1TS2duO
via IFTTT