Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine ( trans- 2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is S2157 ; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Here, using an in silico hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of S2157 derivatives characterized by modifications of the benzyloxy and piperazine groups. Among the synthesized derivatives, a compound possessing 2-fluoropyridine and 2,8-diaza-spiro[4.5]decane groups (compound 10 ) showed the most desirable activities, and its eutomer, S1427 , was isolated by the optical resolution of 10 . In addition to potent LSD1 inhibitory activity, S1427 exhibited desirable hERG channel inhibition and microsomal stability profiles.