Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators

Tumor
necrosis factor α (TNFα) plays a critical role
in inflammatory and autoimmune diseases. While biologic drugs have
improved patient outcomes in conditions like rheumatoid arthritis
by disrupting TNFα signaling, small molecule targeting has been
challenging due to the strong TNF-receptor binding and difficulty
in disrupting the TNF trimer. This research presents small molecule
TNFα inhibitors with a novel bridged-piperazine core, developed
through molecular dynamics simulation and scaffold hopping. The initial
hit was optimized using structure-based design, leading to the discovery
of a lead molecule with similar potency to the prototype but enhanced
physicochemical properties. This lead demonstrated oral efficacy in
a mouse glucose-6-phosphate isomerase-induced paw swelling model,
comparable to the effects of a TNFα antibody. The estimated
effective human dose is 200 mg once daily, highlighting the potential
for clinical development of these compounds.