Targeting Ubiquitin-Specific Protease 7 with Novel 5-Amino-Pyrazole Inhibitors: Design, Synthesis, and Biological...

Area of Science:

• Medicinal Chemistry
• Enzyme Inhibition
• Drug Discovery

Background:

• Ubiquitin-specific protease 7 (USP-7) is a key target in various diseases.
• Structure-activity relationships (SARs) of USP-7 inhibitors require further exploration.
• Previous lead compound STIRUR-41 provides a basis for developing novel inhibitors.

Purpose of the Study:

• To design and synthesize novel 5-aminopyrazole derivatives.
• To evaluate the inhibitory potential of these derivatives against USP-7.
• To extend the SARs of USP-7 inhibitors.

Main Methods:

• Synthesis of 5-aminopyrazole library (compounds 1a-d and 2a-d).
• Confirmation of chemical structures using NMR and X-ray crystallography.
• In vitro enzymatic assays to determine IC50 values.
• Cytotoxicity assays and permeability studies (PAMPA).
• Molecular docking and dynamics simulations.

Main Results:

• Compounds 1a-d exhibited dose-dependent inhibition of USP-7 with lower IC50 values than STIRUR-41.
• Compound 1d, featuring a meta-trifluoromethylphenyl group, was the most potent inhibitor.
• Compounds from series 2 showed no activity due to steric hindrance.
• Series 1 compounds were non-cytotoxic across various cell lines at 10 μM.
• Compound 1d displayed favorable permeability characteristics.

Conclusions:

• Novel 5-aminopyrazoles are effective USP-7 inhibitors.
• Compound 1d represents a promising lead candidate for further development.
• SAR insights indicate that steric hindrance negatively impacts USP-7 inhibition.
• The developed compounds show potential for therapeutic applications with good safety profiles.