Discovery of orally active 1,4,5,6,8-pentaazaacenaphthylens as novel, selective, and potent covalent BTK inhibitors for the treatment of rheumatoid arthritis.

Bruton's tyrosine kinase (BTK) plays a crucial role in adaptive and immune responses by modulating B-cell, Fc, toll-like, and chemokine receptor signaling pathways. BTK inhibition is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. The development of novel, highly selective, and less toxic BTK inhibitors may be beneficial for the treatment of autoimmune diseases with unmet medical needs. In this study, structure-based drug design was used to discover a series of novel, potent, and selective covalent BTK inhibitors with a 1,4,5,6,8-pentaazaacenaphthylen scaffold. Among them, compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel BTK inhibitor requiring further development for the treatment of autoimmune diseases.