Check patentability & draft patents in minutes with Patsnap Eureka AI!

Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (PKAN) and methods for the synthesis of such compounds

a technology of pantothenate kinase and derivatives, applied in the field of pantetheine derivatives, can solve the problems of limited analytical techniques, hampered use and testing of phosphorylated derivatives of pantothenate and pantetheine, and insufficient description of procedures, etc., to achieve less side effects, reduce toxicity, and effective treatment of disease

Inactive Publication Date: 2018-05-03
UNIVERSITY OF GRONINGEN +2
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent aims to provide new compounds that can treat neurodegenerative diseases such as PKAN. These compounds are needed because current treatments have limited effectiveness or can cause harmful side effects. The new compounds should have improved stability and reduced toxicity in humans. The invention is focused on finding new molecular structures that can effectively treat these diseases.

Problems solved by technology

The use and testing of phosphorylated derivatives of pantothenate and pantetheine is hampered by a lack of suitable methods of preparation and purification procedures.
Most research on the synthesis of various phosphorylated pantothenic acid derivatives has been done a long time ago, when the availability of analytical techniques was limited.
Moreover, in most cases the procedures are not well described and their reproducibility is questionable (King, T. E. et al.
Although pantethine is a potent compound rescuing the Drosophila PKAN model, in serum pantethine is rapidly converted by pantetheinases to vitamin B5 and cysteamine (Wittwer et al., J. Clin. Invest., 1985, 76, 1665) and therefore the compound pantethine is less likely to be an effective treatment for PKAN.
In particular, it has not been suggested that such compounds could be useful in the treatment of neurodegenerative diseases, such as PKAN.
However, an economically viable chemical synthesis method, or a possible medical use have not been reported for this compound.
However, a pharmaceutical use of this compound was not envisaged.
The medical use of phosphorylated compounds was often found to be limited by the compounds' poor ability to penetrate cell membranes.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (PKAN) and methods for the synthesis of such compounds
  • Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (PKAN) and methods for the synthesis of such compounds
  • Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (PKAN) and methods for the synthesis of such compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (S)-acyl-4 ‘-phosphopantetheines

[0110]Pantothenic acid was enzymatically converted to 4′-phosphopantothenate. Isolated 4′-phosphopantothenic acid was then reacted with (S)-substituted mercaptoethylamines in the presence of a coupling reagent and an activator in a solvent. (S)-trityl-4′-phosphopantetheine obtained this way was isolated from the reaction mixture, followed by its conversion to 4′-phosphopantetheine. Finally, 4′-phosphopantetheine was converted to (S)-acyl-4′-phosphopantetheine by thioesterification with the corresponding thioacid, such as thioacetic acid. In one example, the phosphate group was masked by esterification, to improve the membrane penetration potential of the compound. Masking the phosphate group was effected by the formation of phosphate esters from (S)-acyl-4′-phosphopantetheine with the corresponding halomethyl ester of the carboxylic acid, such as chloromethyl pivalate, iodomethyl pivalate, chloromethyl acetate and iodomethyl acetate.

example 2

Increased Stability of 4′-phosphopantetheine and (S)-acetyl-4′-phosphopantetheine in Serum as Compared to Pantethine

[0111]This example shows the superior stability of (S)-acetyl-4′-phosphopantetheine and 4′-phosphopantetheine in fetal calf serum (FCS) in comparison to pantethine.

[0112]Pantethine has been shown to be rapidly converted in serum by pantetheinases to vitamin B5 and cysteamine (Wittwer et al., 1985, 76, 1665). We synthesized (S)-acetyl-4′-phosphopantetheine and 4′-phosphopantetheine as described in Example 1 and subsequently evaluated the stability of these compounds in FCS.

[0113]Materials and Methods: Pantethine (purchased from Sigma), (S)-acetyl-4′-phosphopantetheine and 4′-phosphopantetheine were incubated at a final concentration of 1 mM in FCS and in PBS for 30 minutes at 37° C. After incubation, the samples were processed to remove proteins and HPLC analysis was used to assess the amount of remaining compound indicating the stability of the respective compounds.

[01...

example 3

Rescue Potential of 4′-phosphopantetheine and (S)-acetyl-4′-phosphopantetheine in Cellular PKAN Disease Model

[0115]The down-regulation of dPANK / fbl (PANK ortholog in Drosohila) using RNAi approach in Drosophila S2 cells is an established in-vitro PKAN disease model (Rana, A. et al., PNAS, 2010, 107, 6988; Siudja et al., EMBO Mol med. 2011, 3, 755; Siudeja et al., PLoS One 2012, 7, e443145). Down-regulation of dPANK / fbl by RNAi, causes a decrease in the survival of cells. A rescuing compound such as pantethine, 4′-phosphopantetheine or (S)-acetyl-4′-phosphopantetheine restores the cell survival. The following example is included to compare the rescue efficiency of pantethine, (S)-acetyl-4′-phosphopantetheine and 4′-phosphopantetheine in such model system.

[0116]Materials and Methods: Drosophila Schneider's S2 cells were cultured and subjected to RNAi treatment as described previously (Rana, A. et al., 2010, 107, 6988.). 100 μM of pantethine, (S)-acetyl-4′-phosphopantetheine and 4′-pho...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
pharmaceutical compositionaaaaaaaaaa
Login to View More

Abstract

The invention relates to (S)-acyl-4′-phosphopantetheine derivatives, methods of their synthesis, and related medical uses of such compounds. Preferred medical uses relate to the treatment of neurodegenerative diseases, such as PKAN.

Description

RELATED APPLICATION[0001]This application is a division of U.S. application Ser. No. 15 / 034,244 (now allowed), filed May 4, 2016, which is a U.S. National Phase application, filed under 35 U.S.C. § 371, of International Application No. PCT / EP2014 / 073258, filed Oct. 29, 2014, which claims priority to European Application No. 13191457.4, filed Nov. 4, 2013, the entire contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to pantetheine derivatives, their synthesis and medical uses thereof.BACKGROUND OF THE INVENTION[0003]Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic neurodegenerative disease. The disease is caused by mutations in the gene coding for pantothenate kinase 2 (PANK2). Pantothenate kinase 2 phosphorylates pantothenate to 4′-phosphopantothenate in the de novo biosynthesis pathway of coenzyme A. In PKAN patients, PANK2 (one of the four PANK isoforms known in humans and localized to ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): C07F9/09
CPCC07F9/091A61P25/08A61P25/28A61P35/00A61P43/00
Inventor JENKO, BRANKOKOSEC, GREGORPETKOVIC, HRVOJEBERKE, AJDA PODGORSEKPAHOR, JERCACUSAK, ALENSIBON, ODA CORNELIA MARIASRINIVASAN, BALAJI
Owner UNIVERSITY OF GRONINGEN
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com