Oxadiazole inhibitors of HIPK2 for treating kidney fibrosis
Inventors
He, John Cijiang • Liu, Ruijie • Das, Bhaskar • Xiao, Wenzhen • LI, Zhengzhe • Lee, Kyung
Assignees
University of Kansas • US Department of Veterans Affairs
Publication Number
US-10669266-B2
Publication Date
2020-06-02
Expiration Date
2038-01-05
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Abstract
Compounds that are selective inhibitors of Smad3 activation are disclosed. The compounds have the following structure: in which Z is an oxadiazole. The compounds disclosed are useful in treatment of fibrotic disease, particularly renal fibrosis, and similar diseases associated with the dysregulation of the HIPK2/Smad3 signaling pathway.
Core Innovation
The invention relates to compounds that are selective inhibitors of Smad3 activation, specifically oxadiazole-based inhibitors of homeodomain interacting protein kinase 2 (HIPK2). The compounds have a defined structure wherein the group Z is an oxadiazole. These compounds are useful in the treatment of fibrotic diseases, particularly renal fibrosis, and conditions associated with the dysregulation of the HIPK2/Smad3 signaling pathway.
The disclosed compounds function by inhibiting the interaction of HIPK2 with Smad3, thereby suppressing Smad3 activation without inhibiting the kinase activity of HIPK2. This mechanism differs from broad HIPK2 inhibition and allows selective blockade of the TGF-β1/Smad3 pro-fibrogenic pathway.
The problem addressed by the invention arises from kidney fibrosis characterized by excessive extracellular matrix deposition leading to loss of kidney function. While kidney disease therapies often focus on removing causal factors, an effective anti-fibrotic agent is needed to restore kidney structure and function. TGF-β1/Smad3 pathway activation is critical to fibrogenesis, with Smad3 highly activated in fibrotic kidneys. Existing HIPK2 inhibitors are limited and may broadly affect HIPK2 functions, including p53 regulation, which may not be beneficial. There is a need for selective inhibitors targeting the HIPK2-Smad3 interaction to provide anti-fibrotic effects without unwanted side effects.
Claims Coverage
The patent contains two independent compound claims (claims 1 and 17) and several independent method claims (claims 9, 10, 15, 18, 19, and 20). Below are the main inventive features extracted from each independent claim.
Compound of formula I
A compound having general formula I in which Z is an oxadiazole, X is N or CH, and substituents R1 and R2 are independently selected from a defined group including hydrocarbyl, halogen, nitro, amino, acyl, sulfonyl, thio, haloalkyl, haloalkoxy, carboxyl, boron-containing groups, and others, with specified variations.
Compound of formula II
A compound having the alternate general formula II as defined in the patent, representing a related oxadiazole structure useful as an inhibitor of HIPK2/Smad3 interaction.
Method for inhibiting HIPK2 interaction with Smad3
A method comprising bringing HIPK2 into contact with a compound of formula I or formula II to inhibit the interaction between HIPK2 and Smad3.
Method for inhibiting Smad3 activation
A method comprising bringing Smad3 into contact with a compound of formula I or formula II to inhibit Smad3 activation.
Method for treating fibrotic disease
A method of treating a fibrotic disease, specifically including renal fibrosis, by administering a compound of formula I or formula II to a subject suffering from the disease.
The claims collectively cover the novel oxadiazole compounds with specific substituent patterns, their pharmaceutical compositions, and methods of using these compounds to selectively inhibit the HIPK2/Smad3 interaction and Smad3 activation, providing treatment for fibrotic diseases such as kidney fibrosis.
Stated Advantages
The compounds selectively inhibit Smad3 activation without inhibiting HIPK2 kinase activity, reducing potential side effects.
They interrupt HIPK2-Smad3 protein-protein interactions, providing a targeted approach to antifibrotic therapy.
The compounds demonstrate efficacy in vitro and in vivo, reducing fibrosis and improving kidney function in animal models.
Treatment with the compounds suppresses pro-fibrotic gene expression and signaling pathways associated with renal fibrosis.
Documented Applications
Treatment of fibrotic diseases, particularly renal fibrosis.
Use as selective inhibitors of the HIPK2/Smad3 signaling pathway to modulate kidney disease progression.
Pharmaceutical compositions comprising the compounds for oral or parenteral administration to patients.
In vitro and in vivo methods for inhibiting HIPK2-Smad3 interaction and Smad3 activation, useful in research and therapeutic contexts.
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