Anti-fibrotic agent
Inventors
Paige, Mikell • Petruncio, Gregory • Shim, Yun Michael
Assignees
UVA Licensing and Ventures Group • George Mason University
Publication Number
US-11666560-B2
Publication Date
2023-06-06
Expiration Date
2040-09-24
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Abstract
Tacrolimus is an immunosuppressant drug. The present disclosure provides an anti-fibrotic agent by transforming Tacrolimus, such that the anti-fibrotic agent is used for treating fibrosis. The anti-fibrotic agent is not immunosuppressant. In one embodiment, the present invention provides a method to transform Tacrolimus into an anti-fibrotic agent.
Core Innovation
The invention provides an anti-fibrotic agent derived from Tacrolimus (FK506) that does not have immunosuppressive activity and is used for treating fibrosis, particularly idiopathic pulmonary fibrosis (IPF). The invention involves the transformation of FK506 into a compound known as CT474, which comprises a peptidyl-prolyl cis-trans isomerase (PPIase) binding domain (specifically, a FKBP binding domain) and a blocked calcineurin binding domain. This transformation is achieved through a Heck reaction.
The problem addressed by the invention is the lack of effective therapies for IPF, which is a chronic and fatal disease characterized by progressive fibrosis of the lungs. Existing immunosuppressant drugs, including Tacrolimus, are unsuitable for long-term anti-fibrotic use due to their broad immunosuppressive effects and associated side effects such as increased susceptibility to infections and other complications. There is a specific need for compounds that can reduce or reverse fibrosis without causing immunosuppression.
The invention achieves this by producing CT474, which retains anti-fibrotic properties while eliminating immunosuppressive effects. CT474 is configured to reduce fibrosis by inhibiting the stabilization of collagen in the subject and exhibits the ability to bind FKBP (FK506-binding protein) while having a blocked calcineurin binding domain. The compound can be further characterized by its synthesis via Heck reaction using FK506 and an unsaturated halide in the presence of a palladium catalyst, resulting in a yield of about 50% to 95% after purification.
Claims Coverage
The patent includes three independent claims that establish inventive features related to anti-fibrotic therapy using a modified FK506 compound and its production process.
Method for treating pulmonary fibrosis using a compound with a PPIase binding region and a blocked calcineurin binding region
A method to treat pulmonary fibrosis by administering to a mammalian subject a compound configured to reduce fibrosis, wherein the compound has a peptidyl-prolyl cis-trans isomerase binding region (including a FKBP binding region) and a blocked calcineurin binding region, may also have a solvent accessible region, and is represented by Formula II.
Compound with a PPIase binding region and a blocked calcineurin binding region
A compound comprising a peptidyl-prolyl cis-trans isomerase binding region (including a FKBP binding region) and a blocked calcineurin binding region, and optionally a solvent accessible region, wherein the compound is represented by Formula II.
Method for synthesizing the compound via Heck reaction
A method comprising obtaining FK506 or its analogue and transforming it using a Heck reaction to form a compound represented by Formula II, where the synthesized compound comprises a FKBP binding region and a blocked calcineurin binding region, and optionally a solvent accessible region.
The inventive features broadly cover the use, composition, and synthesis of a modified FK506 compound for treating pulmonary fibrosis, characterized by a PPIase (FKBP) binding region and a blocked calcineurin binding region, and methods of producing such compounds via Heck reaction.
Stated Advantages
Provides an anti-fibrotic agent for treating fibrosis, particularly IPF, that does not cause immunosuppression.
Reduces fibrosis and can potentially stop or reverse the effects of IPF.
Retains FKBP binding activity while eliminating calcineurin inhibition activity, avoiding side effects of traditional immunosuppressants.
Documented Applications
Treatment of fibrosis, more particularly idiopathic pulmonary fibrosis (IPF), in mammalian subjects.
Use in pharmaceutical compositions for the treatment of IPF and related fibrotic diseases.
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