Cyclopropanamine Compounds and Use Thereof

Benjamin Blass

doi:10.1021/acsmedchemlett.5b00422

editorial

. 2015 Dec 1;7(1):10–11. doi: 10.1021/acsmedchemlett.5b00422

Cyclopropanamine Compounds and Use Thereof

Benjamin Blass ^1,^*

PMCID: PMC4716593 PMID: 26819657

Title:	Cyclopropanamine Compounds and Use Thereof
Patent Application Number:	WO2015156417Al	Publication date:	October 15th, 2015
Priority Application:	JP2014-082057	Priority date:	April 11th, 2014
Inventors:	Matsumoto, S.; Hattori, Y.; Toyofuku, M.; Morimoto, S.; Daini, M.; Kojima, T.; Kaku, T.; Ito, M.
Assignee Company:	Takeda Pharmaceuticals
Disease Area:	CNS	Biological Target:	Lysine-specific demethylase-1
Summary:	Packaging of DNA into nucleosomes in eukaryotic cells is dependent upon the proper utilization of histones. These highly basic proteins are the primary component of chromatin, act as spool for DNA winding, and are regulated via methylation and demethylation processes. Lysine-specific demethylase 1 (LSD1) is an FAD dependent enzyme that demethylates mono- and dimethylated lysines in histone 3. Inhibition of this enzyme causes an increase in histone 3 methylation. Further, changes in methylation content of histone 3 have been linked to alterations in gene expression. LSD1 inhibitors are currently being examined as novel therapeutic agent for the treatment of a number of disease states including schizophrenia, Rett’s syndrome, fragile X syndrome, Alzheimer’s disease, epilepsy, and drug addiction. The present disclosure describes a series of functionalized cyclopropanamine inhibitors of LSD1 and their method use in treating the aforementioned conditions.
Important Compound Classes:
Definitions:	A is an optionally substituted heterocyclic group, or an optionally substituted hydrocarbon group;
	B is a ring selected from
	(1) a 5- or 6-membered aromatic heterocycle optionally fused with an optionally substituted 5- or 6-membered ring, and (2) a benzene ring fused with an optionally substituted 5- or 6-membered ring, wherein the ring represented by B is optionally substituted and binds, via two adjacent carbon atoms with one atom in between, to a group represented by the formula and a group represented by the formula
	R¹, R², R³, and R⁴ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
	A and R¹ are optionally bonded with each other to form, together with the adjacent nitrogen atom, an optionally substituted cyclic group; and R² and R³ are optionally bonded with each other to form, together with the adjacent nitrogen atom, an optionally substituted cyclic group, or a salt thereof.
Key Structures:
Recent Review Articles:	Lysine Demethylases Inhibitors, Suzuki T.; Miyata N.. Journal of Medicinal Chemistry; 2011, 54, (24), , 8236–8250.
	Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy, Chen Y.; Jie W.; Yan W.; Zhou K.; Xiao Y.. Critical reviews in eukaryotic gene expression; 2012, 22, (1), , 53–9.
	Lysine-specific demethylase 1 as a potential therapeutic target, Stavropoulos P.; Hoelz A.. Expert opinion on therapeutic targets; 2007, 11, (6), , 809–20.
Biological Assay:	Lysine-specific demethylase-1 (LSD1) inhibition assay: A test compound dissolved in DMSO was added to a reaction solution (50 mM Tris-HCl (pH 8.O), 0.1% BSA, 1 mM DTT) containing LSD1 enzyme, and the mixture was reacted at room temperature for 60 min. Biotin-histone H3 mono methylated K4 peptide solution (NH₂-ART(meK)QTARKSTGGKAPRKQLAGGK(Biotin)-CONH₂) was added to start the reaction. After reaction at room temperature for 5 min, 2-PCPA solution was added to terminate the reaction. A detection solution (800 mM potassium fluoride, 0.1% BSA) containing europium-labeled antihistone H3 antibody (Wako Pure Chemical Industries, Ltd.) and Streptavidin-XL665 (Cisbio) was further added, and the mixture was left standing for 60 min. A time-resolved fluorescence (excitation 320 nm, emission 615 nm, 665 nm) was measured by Envision (PerkinElmer). The LSD1 inhibitory rate (%) of the test compound was calculated by the following formula:
	inhibitory rate (%) = (1 – (test compound count – blank)/(control – blank)) × 100
	The count of the LSDl enzyme reaction mixture under compound nonaddition conditions is indicated as control, and the count under compound nonaddition and LSD1 enzyme nonaddition conditions is indicated as blank. A concentration necessary for achieving 50% inhibitory rate was taken as IC₅₀ value.
Biological Data:	Lysine-specific demethylase-1 (LSD1) inhibition assay
Claims:	20 total claims
	16 composition of matter claims
	4 method of use claims