title: Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors.
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(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.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiao
authors.affiliation: School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ni
authors.affiliation: School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China.
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Xu
authors.affiliation: School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Tong
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Tong-Tian
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China. Electronic address: czliao@hfut.edu.cn.
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Liao
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China. Electronic address: ahmupharm@126.com.
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Tang
mesh_terms: D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; C000612891:pyrazolo(1,5-d)(1,4)benzoxazepin-5(6H)-one; D008995:Monoamine Oxidase
keywords: Anti-Parkinson; Benzoxazepinone; Isoform selectivity; Selective hMAO-B inhibitor; hMAO