C–H activation enables a rapid structure–activity relationship study of arylcyclopropyl amines for potent and selective LSD1 inhibitors

Abstract

We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.

Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A)

“…Meanwhile, the addition of methoxy, fluoro or trifluoromethyl groups to the phenyl ring of tranylcypromine is known to boost LSD1 inhibition. 14,19,24 We found that introduction of these substituents restored the ability to significantly inhibit LSD in the fluorinated analogues 7g, 9a, 9c, 9d and 10d. Finally, tranylcypromine analogues containing the Cl, NO 2 or SF 5 substituents are undisclosed as LSD1 inhibitors in the literature.…”

“…Meanwhile, as tranylcypromine itself is relatively modest in LSD1 inhibition (IC 50 ~ 25 µM), medicinal chemistry efforts have focused on second-generation analogues with higher potency. [8][9][10][11][12][13][14][15][16][17][18][19][20] Despite the mechanistic similarity between amine oxidases, the structure-activity relationships among tranylcypromine analogues is distinct for MAOs versus LSD1. For example, we found that a cyclopropylamine bearing an alkoxy substituent in lieu of the aromatic ring in 1 was a nanomolar MAO inhibitor but inactive against LSD1.…”

Drug Design Concepts for LSD1‐Selective Inhibitors

“…Therefore, TGS could be a powerful strategy for drug discovery. Using TGS strategies, we have identified several epigenetic modulators including HDAC inhibitors,, SIRT inhibitors, and LSD1 inhibitors . In this section, we highlight the discovery of LSD1‐selective inhibitors using TGS strategies based on our original ideas.…”

“…Recently, it has been reported that NCD38 ( 16d ) showed unique anticancer activities against leukemia and glioma ,. The optimization studies of the phenyl ring of the PCPA part of 16d were performed to improve the LSD1 inhibitory activity and anticancer activity of 16d . A series of 16d derivatives were rapidly synthesized using a new synthetic strategy for trans ‐2‐arylcyclopropylamine (ACPA), in which a sequential coupling reaction with C−H borylation and Suzuki coupling reported by Itami and Yamaguchi group was performed .…”

Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

“…In the LSD1•MC2580/14e structure, one phenylalanine in the linear extension occupies the position of T3 in the LSD1•H3 structure, and the other branched phenyl ring occupies the same position as the ortho -benzyloxy group of S1201. Other para -substituted inhibitors include the following: OG-L002 (Table 2), which inhibits viral infection; 78 pan-histone demethylase inhibitors that are hybrids of 2-PCPA and Jumonji C-containing KDM inhibitors; 79 compounds coupled with hydroxycinnamic acid; 80 and biphenyl derivatives 81 …”