New Drug Approvals

Home » 0rphan drug status » Pracinostat

Pracinostat

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,777,596 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,071 other followers

add to any

Share

Pracinostat.svg

ChemSpider 2D Image | Pracinostat | C20H30N4O2

Pracinostat.png

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
Image result for S*BIO
str1
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.

Image result for University of Queensland

University of Queensland

Image result for MEI Pharma

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.

Image result for Canadian Cancer Society Research Institute

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).

Image result for HELSINN

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

Figure

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 ChenWeiping DengKanda SangthongpitagHong Yan SongEric T. SunNiefang YuYong Zou
Applicant S*Bio Pte Ltd

Scheme I

Figure imgf000041_0001

Scheme II

Figure imgf000042_0001Scheme III

Figure imgf000043_0001Scheme IV

Figure imgf000044_0001 Scheme V

Figure imgf000045_0001

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.201154 (13), pp 4694–4720
DOI: 10.1021/jm2003552
Phone: +65-68275019. Fax: +65-68275005. E-mail: haishan_wang@sbio.com.

Abstract

Abstract Image

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 (t1/2), 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 δN = 169.0 ppm (CONHOH). Other nitrogens in 3were identified by 1H–15N HMBC (DMSO-d6) with δN 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 δN = 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 ChenWeiping DengKen Chi Lik LeePek Ling LyeEric T. SunHaishan WangNiefang Yu
Applicant S*Bio Pte Ltd

SEE

WO 2008108741

WO 2014070948

Patent

WO-2017192451

References

  1. Jump up^ “In vitro enzyme activity of SB939 and SAHA”. 22 Aug 2014.
  2. 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 Journaldoi:10.1038/bcj.2012.14.
  3. 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 Therdoi:10.1158/1535-7163.MCT-09-0689.
PATENT 
Cited Patent Filing date Publication date Applicant Title
WO2005028447A1 * Sep 21, 2004 Mar 31, 2005 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
US20050137234 * Dec 14, 2004 Jun 23, 2005 Syrrx, Inc. Histone deacetylase inhibitors
Reference
1 None
2 See also references of EP1937650A1
Citing Patent Filing date Publication date Applicant Title
WO2009084544A1 * Dec 24, 2008 Jul 9, 2009 Idemitsu Kosan Co., Ltd. Nitrogen-containing heterocyclic derivative and organic electroluminescent device using the same
WO2010043953A2 * Oct 14, 2009 Apr 22, 2010 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2010043953A3 * Oct 14, 2009 Mar 24, 2011 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2017030938A1 * Aug 12, 2016 Feb 23, 2017 Incyte Corporation Heterocyclic compounds and uses thereof
DE102007037579A1 Aug 9, 2007 Feb 19, 2009 Emc Microcollections Gmbh Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe
US8865912 Jan 27, 2014 Oct 21, 2014 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9024029 Sep 3, 2013 May 5, 2015 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9062003 Sep 9, 2014 Jun 23, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797 May 15, 2015 Oct 13, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9402829 Feb 20, 2015 Aug 2, 2016 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713 Jun 10, 2016 Aug 1, 2017 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
Patent ID

Patent Title

Submitted Date

Granted Date

US2016158186 USE OF DIANHYDROGALACTITOL AND ANALOGS AND DERIVATIVES THEREOF TO TREAT RECURRENT MALIGNANT GLIOMA OR PROGRESSIVE SECONDARY BRAIN TUMOR
2015-04-09
2016-06-09
US2015051288 Methods and Compositions for Treatment of Autism
2014-10-10
2015-02-19
US2017128534 TREATING ROTATOR CUFF CONDITIONS
2015-07-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2014235649 USE OF PHOSPHATASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS TO TREAT DISEASES CHARACTERIZED BY LOSS OF PROTEIN FUNCTION
2012-05-24
2014-08-21
US2013102595 TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
2012-10-15
2013-04-25
US9624515 System and Method of Producing Volatile Organic Compounds from Fungi
2013-02-01
2013-05-30
US2014349938 METHODS OF DIAGNOSING AND TREATING AMYOTROPHIC LATERAL SCLEROSIS
2012-06-01
2014-11-27
US2017100354 COMPOSITIONS AND METHODS FOR TREATING KABUKI SYNDROME AND RELATED DISORDERS
2015-05-29
Patent ID

Patent Title

Submitted Date

Granted Date

US9387263 RbAp48 TRANSGENIC MICE FOR DRUG DISCOVERY IN AGE-RELATED MEMORY DECLINE
2012-08-02
2014-10-02
US2014051716 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2012-03-09
2014-02-20
US2010098691 COMBINATION OF BENZIMIDAZOLE ANTI-CANCER AGENT AND A SECOND ANTI-CANCER AGENT
2010-04-22
US2016069887 BIOMARKERS FOR PROGNOSIS
2014-04-08
2016-03-10
US8937050 Methods and compositions for treatment of autism
2012-10-31
2015-01-20
Patent ID

Patent Title

Submitted Date

Granted Date

US2017049784 METHOD OF TREATING ACUTE MYELOID LEUKEMIA AND/OR ACUTE LYMPHOBLASTIC LEUKEMIA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017095484 METHOD OF TREATING RESISTANT NON-HODGKIN LYMPHOMA, MEDULLOBLASTOMA, AND/OR ALK+NON-SMALL CELL LUNG CANCER USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017157141 METHOD OF TREATING LEUKEMIA USING PHARMACEUTICAL FORMULATION CONTAINING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2014-11-26
US2015258068 COMBINATION THERAPIES
2013-10-30
2015-09-17
US2015182490 METHODS FOR TREATING TYROSINE-KINASE-INHIBITOR-RESISTANT MALIGNANCIES IN PATIENTS WITH GENETIC POLYMORPHISMS OR AHI1 DYSREGULATIONS OR MUTATIONS EMPLOYING DIANHYDROGALACTITOL, DIACETYLDIANHYDROGALACTITOL, DIBROMODULCITOL, OR ANALOGS OR DERIVATIVES THEREOF
2013-06-24
2015-07-02
Patent ID

Patent Title

Submitted Date

Granted Date

US8143282 Heterocyclic Compounds
2009-02-19
2012-03-27
US2017020874 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2015-12-01
US2017231931 PRODUCTS FOR THE TREATMENT AND PREVENTION OF NEUROLOGICAL DISORDERS COURSING WITH A COGNITION DEFICIT OR IMPAIRMENT, AND OF NEURODEGENERATIVE DISEASES
2015-08-25
US2017273988 METHODS OF TREATING LYMPHOMA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-08-19
US2017095436 METHODS FOR TREATING MENDELIAN DISORDERS OF THE EPIGENETIC MACHINERY
2015-05-29
Pracinostat
Pracinostat.svg
Names
IUPAC name

(E)-3-(2-Butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
Other names

Pracinostat
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
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

 

“NEW DRUG APPROVALS” 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

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,071 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: