New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors

Area of Science:

• Medicinal Chemistry
• Enzyme Inhibitor Development
• Pharmacology

Background:

• Tumor necrosis factor alpha convertase (TACE) is a metalloproteinase crucial for TNFalpha production.
• Existing TACE inhibitors, like Marimastat, exhibit limitations in blood potency and in vivo efficacy.
• Matrix metalloproteinases (MMPs) share structural similarities with TACE, informing inhibitor design.

Purpose of the Study:

• To synthesize and evaluate novel succinate-based hydroxamic acid derivatives with improved TACE inhibitory activity.
• To investigate the impact of bulky alpha-substituents on TACE inhibition and pharmacokinetic properties.
• To identify optimized TACE inhibitors with enhanced potency and blood bioavailability.

Main Methods:

• Chemical synthesis of novel succinate-based hydroxamic acids incorporating thioether, sulfonamide, and ether substituents.
• In vitro enzymatic assays to determine TACE inhibitory concentration 50 (IC50) values.
• Assessment of inhibitor potency in blood and evaluation of in vivo properties.

Main Results:

• Thioether and ether substituents improved TACE potency but not blood potency compared to Marimastat.
• Sulfonamide derivatives demonstrated enhanced potency against TACE and in blood.
• Optimization of sulfonamides led to potent heterocyclic bicyclic compounds, such as 3t, with nanomolar TACE IC50 and sub-micromolar blood IC50.

Conclusions:

• Bulky alpha-substituents, particularly sulfonamides, represent a promising strategy for developing potent TACE inhibitors.
• Heterocyclic bicyclic sulfonamides show significant potential for improved therapeutic efficacy in TACE-mediated conditions.
• Further development of these optimized TACE inhibitors warrants investigation for their in vivo performance.