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Novel spirocyclic tranylcypromine derivatives as lysine-specific demethylase 1 (LSD1) inhibitors

Author:
Shi, Ying, Wu, Yan-Ran, Su, Ming-Bo, Shen, Dong-Hao, Gunosewoyo, Hendra, Yang, Fan, Li, Jia, Tang, Jie, Zhou, Yu-Bo, Yu, Li-Fang
Source:
RSC advances 2018 v.8 no.3 pp. 1666-1676
ISSN:
2046-2069
Subject:
amines, enzymes, lysine, moieties
Abstract:
Herein we describe the design, synthesis, and biological evaluation of a novel series of tranylcypromine-based LSD1 inhibitors via conformational restriction using spiro ring systems. A simple, direct spirocyclic analog of tranylcypromine (compounds 8a and 8b) was shown to be a 28- to 129-fold more potent inhibitor of LSD1 enzyme compared to tranylcypromine. Further incorporation of various substituted benzyl groups to the amino group resulted in a suite of 2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-amines that are potent LSD1 inhibitors with excellent selectivity profiles (e.g.14a, 15b, 16a, 19a and 20b) against closely related enzymes such as MAO-A, MAO-B, and LSD2.
Agid:
6182102