Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators

Area of Science:

• Immunology
• Medicinal Chemistry
• Pharmacology

Background:

• Tumor necrosis factor α (TNFα) is a key mediator in inflammatory and autoimmune diseases.
• Biologic drugs targeting TNFα have shown efficacy but face challenges in small molecule development.
• Disrupting TNFα signaling via small molecules is difficult due to strong receptor binding and trimer stability.

Purpose of the Study:

• To discover and develop novel small molecule inhibitors of TNFα.
• To overcome challenges associated with targeting TNFα with small molecules.
• To identify compounds with potential for oral administration and clinical development.

Main Methods:

• Utilized molecular dynamics simulations and scaffold hopping for initial hit discovery.
• Employed structure-based design for lead optimization.
• Evaluated oral efficacy in a mouse model of inflammation (glucose-6-phosphate isomerase-induced paw swelling).

Main Results:

• Identified a novel small molecule TNFα inhibitor with a bridged-piperazine core.
• Optimized lead molecule demonstrated comparable potency to the prototype with improved physicochemical properties.
• The lead compound showed significant oral efficacy in vivo, comparable to a TNFα antibody.
• Estimated effective human dose of 200 mg once daily.

Conclusions:

• Novel small molecule TNFα inhibitors with a bridged-piperazine core have been successfully developed.
• These inhibitors possess favorable physicochemical properties and demonstrate oral efficacy.
• The findings support the clinical development potential of these small molecules as an alternative therapeutic strategy for TNFα-mediated diseases.