Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches

Scaffold
hopping and structure-based drug design were employed
to identify substituted 4-aminoquinolines and 4-aminonaphthyridines
as potent, small molecule inhibitors of tumor necrosis factor alpha
(TNFα). Structure–activity relationships in both the
quinoline and naphthyridine series leading to the identification of
compound 42 with excellent potency and pharmacokinetic
profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation
experiments clearly demonstrate that these inhibitors distort the
TNFα trimer upon binding, leading to aberrant signaling when
the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic–pharmacodynamic
activity of compound 42 in a TNF-induced IL-6 mouse model
and in vivo activity in a collagen antibody-induced arthritis model,
where it showed biologic-like in vivo efficacy, will be discussed.