Pracinostat

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ChemSpider 2D Image | Pracinostat | C20H30N4O2

2D chemical structure of 929016-96-6

Pracinostat

Molecular Formula C₂₀H₃₀N₄O₂
Average mass 358.478 Da

2-Propenamide, 3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxy-, (2E)-

929016-96-6 [RN]

SB939

(2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1,3-benzodiazol-5-yl}-N-hydroxyprop-2-enamide

N-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-indole-6-carboxamide

PCI 34051, UNII: GPO2JN4UON

929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
929016-96-6 (free base)
929016-97-7 (trifluoroacetate)

S*BIO (Originator)

Leukemia, acute myeloid, phase 3, helsinn

CAS 929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4

E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt

Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.

WO-2017192451 describes Novel polymorphic crystalline forms of pracinostat (designated as Form 3) and their hydrates, processes for their preparation and compositions and combination comprising them are claimed. Also claimed is their use for inhibiting histone deacetylase and treating cancer, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), breast cancer, colon cancer, prostate cancer, pancreas cancer, leukemia, lymphoma, ovary cancer, melanoma and neuroblastoma.

See WO2014070948 , Helsinn , under sub-license from MEI Pharma (under license from S*Bio), is developing pracinostat, an oral HDAC inhibitor, for treating hematological tumors, including AML, MDS and myelofibrosis.

The oncolytic agent pracinostat hydrochloride is an antagonist of histone deacetylase 1 (HDAC1) and 2 (HDAC2) that was discovered by the Singapore-based company S*BIO. Helsinn obtained the exlusive development and commercialization rights in July 2016, and is conducting phase III clinical trials in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia. Phase II trials are also under way for the treatment of previously untreated intermediate-2 or high risk myelodysplastic syndrome patients and for the treatment of primary or post essential thrombocythemia/polycythemia vera) in combination with ruxolitinib.In North America, S*BIO had been conducting phase II clinical trials of pracinostat hydrochloride in patients with solid tumors and for the treatment of myeloproliferative diseases and phase I clinical trials in patients with leukemia; however, recent progress reports are not available at present. The University of Queensland had been evaluating the compound in preclinical studies for malaria.

University of Queensland

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MEI Pharma

The Canadian Cancer Society Research Institute (the research branch of the Canadian Cancer Society upon its integration with the National Cancer Institute of Canada to form the new Canadian Cancer Society) is conducting phase II clinical trials in Canada for the treatment of recurrent or metastatic prostate cancer.

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Canadian Cancer Society Research Institute

In 2012, the product was licensed to MEI Pharma by S*BIO on a worldwide basis. In 2016, MEI Pharma and Helsinn entered into a licensing, development and commercialization agreement by which Helsinn obtained exclusive worldwide rights (including manufacturing and commercialization rights).

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HELSINN

In 2014, the FDA assigned an orphan drug designation to MEI Pharma for the treatment of acute myeloid leukemia. In 2016, the product received breakthrough therapy designation in the U.S. in combination with azacitidine for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are older than 75 years of age or unfit for intensive chemotherapy.

Pracinostat is an orally available, small-molecule histone deacetylase (HDAC) inhibitor with potential antineoplastic activity. Pracinostat inhibits HDACs, which may result in the accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; the tumor suppressor protein-mediated inhibition of tumor cell division; and, finally, the induction of tumor cell apoptosis. This agent may possess improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors.

Pracinostat is a novel HDAC inhibitor with improved in vivo properties compared to other HDAC inhibitors currently in clinical trials, allowing oral dosing. Data demonstrate that Pracinostat is a potent and effective anti-tumor drug with potential as an oral therapy for a variety of human hematological and solid tumors

SYNTHESIS

Clinically tested HDAC inhibitors.

Activity

Pracinostat selectively inhibits HDAC class I,II,IV without class III and HDAC6 in class IV,^[1] but has no effect on other Zn-binding enzymes, receptors, and ion channels. It accumulates in tumor cells and exerts a continuous inhibition to histone deacetylase,resulting in acetylated histones accumulation, chromatin remodeling, tumor suppressor genes transcription, and ultimately, apoptosis of tumor cells.^[2]

Clinical medication

Clinical studies suggests that pracinostat has potential best pharmacokinetic properties when compared to other oral HDAC inhibitors.^[3]In March 2014, pracinostat has granted Orphan Drug for acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration.

Clinical Trials

CTID	Title	Phase	Status	Date
NCT03151304	A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes	2	Recruiting	2017-10-27
NCT03151408	An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia	3	Recruiting	2017-10-17
NCT02267278	Ruxolitinib and Pracinostat Combination Therapy for Patients With Myelofibrosis (MF)	2	Active, not recruiting	2017-04-27
NCT01873703	Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome	2	Active, not recruiting	2017-04-21
NCT02118909	Evaluate the Effects of Itraconazole and Ciprofloxacin on Single-Dose PK of Pracinostat in Healthy Nonsmoking Subjects	1	Completed	2017-02-22
NCT02058784	Study to Evaluate the Food Effect of Single-dose Bioavailability of Pracinostat in Healthy Adult Subjects	1	Completed	2017-02-22
NCT01993641	Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA	2	Completed	2017-02-22
NCT01112384	A Study of SB939 in Patients With Translocation-Associated Recurrent/Metastatic Sarcomas	2	Completed	2016-11-25
NCT01184274	A Phase I Study of SB939 in Pediatric Patients With Refractory Solid Tumours and Leukemia	1	Completed	2014-01-16
NCT01200498	Study of SB939 in Subjects With Myelofibrosis	2	Completed	2013-12-13

PATENT

WO2005028447

Inventors	Dizhong Chen, Weiping Deng, Kanda Sangthongpitag, Hong Yan Song, Eric T. Sun, Niefang Yu, Yong Zou,
Applicant	S*Bio Pte Ltd

Scheme I

Scheme II

Scheme III

Scheme IV

Scheme V

PAPER

Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

^†Chemistry Discovery, ^‡Biology Discovery, and ^§Pre-Clinical Development, S*BIO Pte Ltd., 1 Science Park Road, No. 05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore

J. Med. Chem., 2011, 54 (13), pp 4694–4720

DOI: 10.1021/jm2003552

Phone: +65-68275019. Fax: +65-68275005. E-mail: haishan_wang@sbio.com.

http://pubs.acs.org/doi/abs/10.1021/jm2003552

Abstract

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC₅₀), liver microsomal stability (t_1/2), cytochrome P450 inhibitory (3A4 IC₅₀), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

(E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt (3)

The freebase of 3 was prepared according to procedure D. The hydroxamic acid moiety was identified by ¹H–¹⁵N HSQC (DMSO-d₆) with δ_N = 169.0 ppm (CONHOH). Other nitrogens in 3were identified by ¹H–¹⁵N HMBC (DMSO-d₆) with δ_N of 241.4 ppm for N³ of the benzimidazole ring, 152.3 ppm for N¹, and 41.3 ppm for the diethylamino group (reference to nitromethane δ_N = 380.0 ppm in CDCl₃). The dihydrochloride salt of 3 was prepared according to procedure D as white or off-white solid or powder in ∼60% yield from 9 in two steps. LC–MS m/z 359.2 ([M + H]⁺).

¹H NMR (DMSO-d₆) δ 11.79 (brs, 1H, NH or OH), 10.92 (very br s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 5.01 (t-like, J = 7.7 Hz, 2H), 3.48 (m, 2H), 3.30–3.19 (m, 6H), 1.87 (quintet, J = 7.8 Hz, 2H), 1.47 (sextet, J = 7.5 Hz, 2H), 1.29 (t, J = 7.2 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H);

¹³C NMR (DMSO-d₆) δ 162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (br, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2 × CH), 48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.

Anal. (C₂₀H₃₀N₄O₂·2HCl·0.265H₂O) C, H, N, Cl. Water content = 1.09% (Karl Fisher method). HRMS (ESI) m/z [M + H]⁺ calcd for C₂₀H₃₁N₄O₂, 359.2442; found, 359.2449.

PATENT

WO 2007030080

http://google.com/patents/WO2007030080A1?cl=en


Inventors	Dizhong Chen, Weiping Deng, Ken Chi Lik Lee, Pek Ling Lye, Eric T. Sun, Haishan Wang, Niefang Yu,
Applicant	S*Bio Pte Ltd

SEE

WO 2008108741

WO 2014070948

Patent

WO-2017192451

References

Jump up^ “In vitro enzyme activity of SB939 and SAHA”. 22 Aug 2014.
Jump up^ “The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML”. Blood Cancer Journal. doi:10.1038/bcj.2012.14.
Jump up^ Veronica Novotny-Diermayr; et al. (March 9, 2010). “SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer”. Mol Cancer Ther. doi:10.1158/1535-7163.MCT-09-0689.

PATENT

Cited Patent	Filing date	Publication date	Applicant	Title
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Reference
1		None
2		See also references of EP1937650A1

Citing Patent	Filing date	Publication date	Applicant	Title
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Pracinostat
Names

IUPAC name (E)-3-(2-Butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
Other names Pracinostat
Identifiers
CAS Number	929016-96-6
3D model (JSmol)	Interactive image
ChemSpider	25027185
PubChem CID	49855250
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₀H₃₀N₄O₂
Molar mass	358.49 g·mol⁻¹
Density	1.1±0.1 g/cm³
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////Pracinostat, PCI 34051, SB939, orphan drug designation, Leukemia, acute myeloid, phase 3, helsinn

CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)C=CC(=O)NO

“DRUG APPR INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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Pracinostat

Pracinostat

Activity

Clinical medication

Clinical Trials

Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

Abstract

References

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