Substituted (e)-n'-(1-phenylethylidene)benzohydrazide analogs as histone demethylase inhibitors

Abstract

Substituted (E)‑N'‑(1‑phenylethylidene)phenylhydrazide analogs or (3‑(5‑chloro‑2‑hydroxyphenyl)‑4‑methyl‑1H‑pyrazole -1-yl)(3-(morpholinosulfonyl)phenyl)methanone, derivatives thereof, and related compounds are useful as inhibitors of lysine-specific histone demethylases including LSD1 of. Synthetic methods of making the compounds; pharmaceutical compositions comprising the compounds; methods of using the compounds and compositions to treat disorders associated with LSD1 (lysine specific demethylase) dysfunction. A pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, and one or more of the following: (a) at least one agent known to increase the activity of histone demethylase; ( b) at least one agent known to reduce the activity of histone demethylases; (c) at least one agent known to treat disorders of uncontrolled cell proliferation; (d) at least one agent known to treat neurodegeneration (e) instructions for treating neurodegenerative disorders; or (f) instructions for treating disorders associated with uncontrolled cell proliferation.

Description

Background technique [0001] Over the past decade, it has become apparent that epigenetic changes, which alter the activity of genes without altering the DNA sequence, contribute to the development and progression of cancer in conjunction with genetic errors (Tsai, H.C. and Baylin, S.B. Cell Res 2011, 21(3), 502-17; and Fullgrabe, J., Kavanagh, E., and Joseph, B. Oncogene 2011). The regulation of modifications to DNA and DNA-associated proteins has become an area of ​​intense interest, and enzymes involved in these processes have been suggested as a new class of protein targets for drug development. The major proteins associated with DNA are histones. The tails of histones host various post-translational modifications, such as phosphorylation, acetylation, methylation, and ubiquitination, and these modifications, especially acetylation and methylation of lysine residues, are important in the regulation of gene expression. plays a major role in and is often dysregulated in can...

AI Technical Summary

Problems solved by technology

Further, there is a scarcity of compounds that are therapeutically effective in the treatment of cancer and other diseases associated with dysfunction of LSD1 and / or LSD2

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