N-(2-Aminophenyl)-4-([[4-(pyridin-3-yl)pyrimidin-2-yl]amino]methyl)benzamide

N-(2-Aminophenyl)-4-([[4-(pyridin-3-yl)pyrimidin-2-yl]amino]methyl)benzamide Property

Melting point:

>170oC (dec.)

Density 

1.340±0.06 g/cm3(Predicted)

storage temp. 

RT

solubility 

Soluble in DMSO (up to 25 mg/ml)

pka

13.13±0.70(Predicted)

form 

solid

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.

InChI

InChI=1S/C23H20N6O/c24-19-5-1-2-6-21(19)28-22(30)17-9-7-16(8-10-17)14-27-23-26-13-11-20(29-23)18-4-3-12-25-15-18/h1-13,15H,14,24H2,(H,28,30)(H,26,27,29)

InChIKey

HRNLUBSXIHFDHP-UHFFFAOYSA-N

SMILES

C(NC1=CC=CC=C1N)(=O)C1=CC=C(CNC2=NC=CC(C3=CC=CN=C3)=N2)C=C1

Hazard and Precautionary Statements (GHS)

N-(2-Aminophenyl)-4-([[4-(pyridin-3-yl)pyrimidin-2-yl]amino]methyl)benzamide Chemical Properties,Usage,Production

Description

Mocetinostat (726169-73-9) is a class I, isoform-selective HDAC inhibitor, IC50s=0.15, 0.29, 1.66 and 0.59 μM for HDAC1, 2, 3 and 11 respectively.1 Induces hyperacetylation of histones, induces expression of the tumor suppressor p21WAF1 and inhibits proliferation of human cancer cells.2 Mocetinostat displays antifibrotic effects in ischemic heart failure.3 Attenuates the development of hypersensitivity in models of neuropathic pain.4 Active in vivo.5

Uses

Mocetinostat is a multi-targeted histone deacetylase inhibitor used in cancer therapy. Mocetinostat is undergoing clinical trials for the treatment of various cancers including follicular lymphoma, Hodgkin’s lymphoma and acute myelogenous leukemia.

Definition

ChEBI: N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide is a member of benzamides.

Synthesis

To a 2L three-necked round-bottomed flask equipped with a thermometer, a nitrogen introduction tube, a mechanical stirrer, and a dropping funnel was added 4-(((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)benzoic acid (3.40 g, 0.131 mol), o-phenylenediamine (59.3 g, 0.548 mol), 1-hydroxybenzotriazole hydrate (HOBT) (21.7 g 0.156 mol) and DMSO (240 mL). Triethylamine (Et3N) (43.7 mL, 0.313 mol) was added to the stirring mixture at room temperature. The reaction mixture was stirred for 10 minutes, then a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) (30.04 g, 0.156 mol) in DMSO (240 mL) was added in batches of three over 30 minutes at the same temperature. After addition, the reaction mixture was continued to be stirred for 20 h. (The progress of the reaction was monitored by NMR or HPLC to confirm complete consumption of 4-(((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)benzoic acid). Upon completion of the reaction, 30% isopropanol (IPA) aqueous solution (800 mL) was added to the reaction mixture in three portions over 30 minutes. After addition, the reaction mixture formed a suspension, which was cooled to 0-5°C over 45 minutes and stirring was continued at the same temperature for 1 hour. The solid product was collected by diafiltration, washed with 30% aqueous IPA (400 mL) and dried over air to afford the crude product N-(2-aminophenyl)-4-(((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)benzamide (43.04 g, 83% yield).

in vivo

target

HDAC1

IC 50

HDAC1: 0.15 μM (IC₅₀); HDAC2: 0.29 μM (IC₅₀); HDAC11: 0.59 μM (IC₅₀); HDAC3: 1.66 μM (IC₅₀)

References

[1] NANCY ZHOU. Discovery of N-(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an Orally Active Histone Deacetylase Inhibitor[J]. Journal of Medicinal Chemistry, 2008, 51 14: 4072-4075. DOI:10.1021/jm800251w
[2] STÉPHANE RAEPPEL . SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103)[J]. Bioorganic & Medicinal Chemistry Letters, 2009, 19 3: Pages 644-649. DOI:10.1016/j.bmcl.2008.12.048
[3] HIKMET NURAL-GUVENER. Anti-Fibrotic Effects of Class I HDAC Inhibitor, Mocetinostat Is Associated with IL-6/Stat3 Signaling in Ischemic Heart Failure.[J]. International Journal of Molecular Sciences, 2015, 16 5: 11482-11499. DOI:10.3390/ijms160511482
[4] FRANZISKA DENK . HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain[J]. PAIN®, 2013, 154 9: Pages 1668-1679. DOI:10.1016/j.pain.2013.05.021
[5] CLAIRE BONFILS. Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay.[J]. Clinical Cancer Research, 2008, 14 11: 3441-3449. DOI:10.1158/1078-0432.ccr-07-4427