209783-80-2

Basic information

• Product Name: Entinostat
• Synonyms: Carbamic acid, N-[[4-[[(2-aminophenyl)amino]carbonyl]phenyl]methyl]-, 3-pyridinylmethyl ester;entinostat;3-pyridinylmethyl [[4-[[(2-aminophenyl)amino]carbonyl]phenyl]methyl]carbamate, N-(2-Aminophenyl)-4-[N-(pyridine-3ylmethoxycarbonyl)aminomethyl]benzamide;N-[[4-[[(2-Aminophenyl)amino]carbonyl]phenyl]methyl]carbamic acid 3-pyridinylmethyl ester;Entinostat/MS-275;Nsc706995;Entinostat(NSC-706995);MS-275 (Entinostat)
• CAS NO: 209783-80-2
• Molecular Formula: C₂₁H₂₀N₄O₃
• Molecular Weight: 376.4085
• Product Categories: SNDX 275;Entinostat;Inhibitor;API;Inhibitors
• Mol File: 209783-80-2.mol

Chemical Properties

• Melting Point: 159-160 ºC
• Boiling Point: 566.7 °C at 760 mmHg
• Flash Point: 296.6 °C
• Appearance: /solid
• Density: 1.315
• Vapor Pressure: 7.31E-13mmHg at 25°C
• Refractive Index: 1.672
• Storage Temp.: −20°C
• Solubility: DMSO: 38 mg/mL, soluble
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 week.
• CAS DataBase Reference: Entinostat(CAS DataBase Reference)
• NIST Chemistry Reference: Entinostat(209783-80-2)
• EPA Substance Registry System: Entinostat(209783-80-2)

Safety Data

• Hazard Codes: Xi,T
• Statements: 36/37/38-62-48/25-25-61
• Safety Statements: 26-36-45
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 209783-80-2(Hazardous Substances Data)

Usage

Uses

Used in Anticancer Applications:
Entinostat is used as an emerging HDACi for the treatment of solid tumors and hematologic malignancies. It modulates histone deacetylase activity, which can lead to the reactivation of tumor suppressor genes and the suppression of oncogenes, ultimately inhibiting cancer cell growth and proliferation.
Used in Clinical Trials:
Entinostat is currently being evaluated in phase II clinical trials for the treatment of Hodgkin's lymphoma, advanced breast cancer (in combination with aromatase inhibitors), and metastatic lung cancer (in combination with erlotinib). These trials aim to assess the safety, efficacy, and potential synergistic effects of Entinostat when combined with other cancer treatments.

Clinical Use

Entinostat is an HDAC inhibitor with a relatively long half-life (averaging between 33 and 52 hours). Trials have shown significant biological activity in patients with hematological malignancies receiving entinostat treatments. However, the efficacy of entinostat as a single-agent therapy remains limited. Reported dose-limiting toxicities associated with entinostat include neurotoxicity, fatigue, hypophosphatemia, anorexia, and vomiting. The large number of clinical trials using HDAC inhibitors for the treatment of patients with hematological malignancies has demonstrated that these drugs are relatively well tolerated. Although the responses with the currently-available HDAC inhibitors are still limited, there are significant responses in some patients with advanced disease, where options are limited. With better patient selection and the development of more potent HDAC inhibitors, targeting HDACs for the treatment of hematological malignancies remains promising. Furthermore, a growing body of literature suggests that HDAC inhibitors may potentiate some of the currently used cytotoxic or biologic therapies based on their mechanism of action, with multiple trials currently ongoing. Promising combination partners include proteosome inhibitors, DNA demethylating agents, and anthracyclines.

References

1) Hu et al. (2003), Identification of novel isoform-selective inhibitors within class 1 histone deacetylases; J. Pharmacol. Exp. Ther., 307 720 2) Saito et al. (1999), A synthetic inhibitor of histone deacetylase, MS-275, with marked in vivo antitumor activity against human tumors; Proc. Natl. Acad. Sci. USA, 96 4592 3) Eyupoglu et al. (2006), Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275; Mol. Cancer Ther., 5 1248 4) Lee et al. (2001), MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells; J. Pharmacol. Exp. Ther., 307 720 5) Lin et al. (2007), Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents; Br. J. Pharmacol., 150 862 6) Fukuchi et al. (2015), Class I histone deacetylase-mediated repression of the proximal promoter of the Activity-regulated Cytoskeleton-associated Protein Gene regulates its response to brain-derived neurotrophic factor; J. Biol. Chem. 290 6825 [Focus Biomolecules Citation]

InChI:InChI=1/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)

Upstream product

• 56-91-7 p-aminomethylbenzoic acid 
• 95-54-5 1,2-diamino-benzene 
• 530-62-1 1,1'-carbonyldiimidazole 
• 241809-79-0 4-benzoic acid 
• 100-55-0 3-hydroxymethylpyridin 
• 209784-85-0 [2-(4-aminomethylbenzoylamino)phenyl]carbamic acid tert-butyl ester 
• 209784-84-9 tert-butyl-(2-(4-((2,2,2-trifluoroacetamido)methyl)benzamido)phenyl)carbamate 
• 1379471-51-8 C₂₁H₁₈N₆O₃ 
• 1353003-29-8 C₇₂H₆₉N₇O₂₉ 
• 80-73-9 1,3-dimethyl-2-imidazolidinone 
• 212632-27-4 pyridin-3-ylmethyl 1H-imidazole-1-carboxylate 
• 255894-58-7 1-{4-[N-(pyridin-3-ylmethoxycarbonyl)-aminomethyl]benzoyl}imidazole 

Downstream Products

• 1037543-21-7 2-[(tert-butoxy)carbonylamino]-N-{2-[(4-{[(3-pyridylmethoxy)-carbonylamino]methyl}phenyl)carbonylamino]phenyl}acetamide 
• 1037543-24-0 4-{[N-(2-{[4-{[3-pyridylmethoxycarbonylamino]methyl}phenyl]carbonylamino}phenyl)carbamoyloxy]methyl}phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate 
• 1353003-39-0 C₆₆H₆₁N₇O₂₇ 
• 1037543-23-9 (N-{[N-(2-{[4-{[3-pyridylmethoxycarbonylamino]methyl}phenyl]carbonylamino}phenyl)-carbamoyl]methyl}carbamoyloxy)methyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate 
• 1037543-22-8 2-amino-N-{2-[(4-{[(3-pyridylmethoxy)-carbonylamino]methyl}phenyl)carbonylamino]phenyl}acetamide 

Relevant articles and documents

Synthesis of n-substituted benzamide derivatives and their evaluation as antitumor agents

Background: Histone deacetylases inhibitors (HDACIs) with different chemical structures have been reported to play an important role in the treatment of cancer. Objective: The study aims to modify the structure of Entinostat (MS-275) to discover new compounds with improved anti-proliferative activities and perform SAR studies on this class of bioactive compounds. Methods: Fourteen N-substituted benzamide derivatives were synthesized and their antiproliferative activities were tested with four cancer cell lines (MCF-7, A549, K562 and MDA-MB231) by MTT assay. Results: Compared with MS-275, six compounds exhibited comparable or even better antiproliferative activities against specific/certain cancer cell lines. Conclusion: The preliminary SARs showed that (i) the 2-substituent of the phenyl ring in the R group and heteroatoms of amide which can chelate with zinc ion are critical to the antiproliferative activity and (ii) chlorine atom or nitro-group on the same benzene ring largely decreases their anti-proliferative activity. Molecular docking study illustrated the interaction (binding affinity) between the synthesized compounds and HDAC2 was observed to be similar to that of MS-275.

SOLID FORMS OF ENTINOSTAT

Aspects of the present application relate to stable amorphous Entinostat, its amorphous solid dispersion, processes for their preparation and pharmaceutical compositions thereof. Further, aspects relate to crystalline form of Entinostat, process for its preparation and pharmaceutical compositions thereof

CRYSTALLINE FORMS OF ENTINOSTAT

Entinostat is a histone deacetylase inhibitor undergoing clinical investigation in multiple types of solid tumors, such as breast cancer, and hematologic cancers. Crystalline form D and E of Entinostat and crystal form A in high crystal purity are provided. Crystalline form D can be obtained in high chemical purity, exhibits improved water solubility and allows efficient purification of Entinostat with removal of coloured impurities. Processes for the preparation of such crystalline forms and of form A with improved chemical and crystal purity are also provided.

Catalytic Azide Reduction in Biological Environments

In the quest for the identification of catalytic transformations to be used in chemical biology and medicinal chemistry, we identified iron(III) meso-tetraarylporphines as efficient catalysts for the reduction of aromatic azides to their amines. The reaction uses thiols as reducing agents and tolerates water, air, and other biological components. A caged fluorophore was employed to demonstrate that the reduction can be performed even in living mammalian cells. However, in vivo experiments in nematodes (Caenorhabditis elegans) and zebrafish (Danio rerio) revealed a limitation to this method: the metabolic reduction of aromatic azides.

SYNTHESIS METHODS OF HISTONE DEACETYLASE INHIBITORS (HDACIS)

Simple and efficient procedures for the synthesis of histone deacetylase inhibitors. The procedure may provide MS-275 in 72% overall yields.

Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts

We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2 + SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2 + SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.

Method of producing benzamide derivatives

In the case that a selectively monoacylated phenylenediamine derivative which is useful as any of medicines, agricultural chemicals, animal drugs and the intermediates of chemicals is prepared by reacting a benzoic acid derivative with a phenylenediamine derivative, the benzoic acid derivative is converted into a benzoyl imidazole derivative and this benzoyl imidazole derivative is then reaction with the phenylenediamine derivative, whereby the improvement of a preparation efficiency and the high selectivity of the monoacylation can be achieved, the steps of protection and deprotection being omitted.

Cell differentiation inducer

The novel benzamide derivative represented by formula (1) and the novel anilide derivative represented by formula (13) of this invention has differentiation-inducing effect, and are, therefore, useful a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as an anticancer drug, specifically to a hematologic malignancy and a solid carcinoma.

Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives

Newly synthesized benzamide derivatives were evaluated for their inhibitory activity against histone deacetylase. The structure of these derivatives was unrelated to the known inhibitors, and IC50 values of the active compounds were in the range of 2-50 μM. Structure-activity relationship on the benzanilide moiety showed that the 2'-substituent, an amino or hydroxy group, was indispensable for inhibitory activity. Although the electronic influence of the substituent in the anilide moiety showed only a small effect on inhibitory activity, the steric factor in the anilide moiety, especially at positions 3'and 4', played an important role in interaction with the enzyme. Among these benzamide derivatives, MS-275 (1), which showed significant antitumor activity in vivo, has been selected for further investigation.