Home Blog of Signal Transduction TGF-beta/Smad TGF-beta/Smad Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors

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Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors

Inhibition of transforming growth factor β (TGF-β) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-β type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC50 values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model.

 

Comments:

It seems like you've provided information from a scientific study related to the development of potential inhibitors for the treatment of fibrotic diseases and malignant tumors, specifically targeting the transforming growth factor β (TGF-β) type 1 receptor (ALK5). The study involves the design and synthesis of a new series of compounds, with one of them, compound 15r, showing promising results.

Here's a breakdown of the information you provided:

1. **Objective of the Study:**
   - Target: Inhibition of the TGF-β type 1 receptor (ALK5).
   - Purpose: Treatment of fibrotic diseases and malignant tumors.

2. **Design and Synthesis:**
   - New series of compounds: 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives.

3. **Biological Evaluation of Compound 15r:**
   - Inhibition of ALK5 enzyme: IC50 value of 44 nM.
   - Inhibition of NIH3T3 cell viability: IC50 value of 42.5 nM.

4. **Pharmacokinetic Properties of Compound 15r:**
   - Better oral plasma exposure.
   - Excellent bioavailability compared to LY-3200882 (presumably another compound used for comparison).

5. **In Vivo Efficacy:**
   - Inhibition of tumor growth in a CT26 xenograft mouse model.
   - Compound 15r demonstrated a 65.7% reduction in tumor growth.

The study suggests that compound 15r is a potent inhibitor of ALK5, with favorable pharmacokinetic properties and significant efficacy in inhibiting tumor growth in a mouse model. These findings indicate that compound 15r may have potential as a therapeutic agent for fibrotic diseases and malignant tumors, providing a basis for further development and investigation.

Related Products

Cat.No. Product Name Information
S8772 LY 3200882 LY 3200882 is a potent, highly selective inhibitor of TGF-β receptor type 1 (TGFβRI). It potently inhibits TGFβ mediated SMAD phosphorylation in vitro in tumor and immune cells and in vivo in subcutaneous tumors in a dose dependent fashion.

Related Targets

TGF-beta/Smad