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Methods for the treatment of cysteamine sensitive disorders

A sensitivity, cysteamine technology, applied in the combination of syndromes and diseases, in the field of treatment of cysteamine sensitivity symptoms, can solve the inability to deliver cysteamine preparations in clinical development, and incomplete compliance of cystinosis patients Cystamine therapy, drug barriers at therapeutic levels, etc.

Pending Publication Date: 2020-09-18
硫创治疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As a result, many patients with cystinosis do not fully comply with cysteamine therapy and suffer from disease progression as a result
[0006] Clinical development has been hampered by the inability of cysteamine formulations to deliver therapeutic levels of the drug with acceptable toxicology over a sustained period

Method used

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  • Methods for the treatment of cysteamine sensitive disorders
  • Methods for the treatment of cysteamine sensitive disorders
  • Methods for the treatment of cysteamine sensitive disorders

Examples

Experimental program
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Effect test

example 10

[0439] Example 10 describes a rat pharmacokinetic study of a cysteamine precursor in which renal levels of cysteamine following administration of the cysteamine precursor were much higher than those reported after administration of cysteamine bitartrate at 10.5 hours post administration (Dohil et al. Pharmacol. Drug Dev.) "4:170 (2012)).

[0440] Inherited disorders caused by mutations of arginine to cysteine

[0441] Certain genetic diseases can be treated using the methods and compositions of the invention. For example, a disease-causing mutation includes a DNA sequence change that changes the codon for arginine to a codon for cysteine. A subset of such mutations occur in proteins that retain some function, or are at least stable enough to be fully synthesized by the ribosome and transported to their normal destinations (e.g. plasma membrane, mitochondria, nucleus, etc.). Cysteamine can form disulfide bonds with abnormal cysteine ​​residues and, in doing so, somewhat mimic...

example

[0487] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to implement and evaluate the methods and systems claimed herein, and are intended purely to illustrate the invention and are not intended to limit the scope of what the inventors believe to be their invention.

example 1

[0488] Example 1. Efficient synthesis of mixed disulfides

[0489] Multiple research groups have described various methods for the efficient synthesis of mixed disulfides (see Witt et al., Langmuir 23:2318 (2007); Musiejuk et al., Organic Preparations and Procedures (Org. Prep.andProc.)" 47.2:95 (2015)), including methods specifically targeting cysteine ​​and cysteine ​​analogs (eg Szymelfejnik et al. "Synthesis" 22:3528 (2007); Gormer et al. J. Org. Chem. 75.5:1811 (2010)). Recent improvements have been reported, for example based on the use of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to facilitate thiol-disulfide exchange (Musiejuk et al., RSCAdvances )》5.40:31347(2015)).

[0490] These methods allow the preferential synthesis of mixed disulfides (as opposed to two homodimeric disulfides) when combining two different thiols. In this example, the method described by Antoniow et al., Synthesis 3:363 (2007) was used to couple thiol cysteamine and pantetheine. Other thiol ...

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Abstract

The invention features methods for the treatment of cystinosis and other cysteamine sensitive disorders in a subject including administration of a disulfide convertible to cysteamine in vivo. The methods can include the separate administration of a reducing agent to the subject to increase the bioavailablity and extend the plasma pharmacokinetic profile of the cysteamine produced following administration of the disulfide. The methods permit sustained cysteamine plasma concentrations in a subject.

Description

technical field [0001] The present invention provides compositions and methods for treating cysteamine sensitivity symptoms, syndromes and diseases. Background technique [0002] Cysteamine is a naturally occurring aminothiol that is produced in vivo through the catabolism of pantetheine. Preclinical and early clinical studies suggest that cysteamine may be therapeutically active in a variety of diseases, but broad clinical development has been hampered by a lack of convenient dosing regimens and poor toxicology. [0003] Cysteamine has several mechanisms of action, most of which are related to the reducing power of its thiol moiety. Cysteamine was first used in the 1950s as a radioprotectant for cancer patients undergoing radiation therapy and as a treatment for radiation poisoning. The thiol group of cysteamine can contribute to redox homeostasis by reducing free radicals and other oxidative compounds that can be harmful to cells. Cysteamine can also indirectly neutrali...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54C07C323/41C07H15/203
CPCC07C323/25A61P25/00A61K31/164A61K45/06A61K31/145A61K31/375A61K31/355A61K2300/00A61K9/009A61K31/16C07C319/18
Inventor V.P.小斯坦顿P.P.里乌P.巴斯基D.维特
Owner 硫创治疗公司
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