Discovery of 4‑Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton’s Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid Arthritis

A structure-hopping strategy was
applied to discover a series of
novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible
BTK inhibitors. Compared to the previously described cinnoline scaffold
compounds, the 4-aminoquinoline analogues showed significantly improved
drug-like properties, especially in their aqueous solubility. The
most potent compound, 25, displayed a stronger inhibitory
effect on both BTKWT (IC50 =
5.3 nM) and BTKC481S (IC50 =
39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body
weight. On the basis of potency, drug-like properties, stability,
and noncovalent mode of inhibition, our representative inhibitors
could have a promising profile to be treatments for a wide range of
autoimmune diseases.