Synthesis and evaluation of a novel class of spiro[chromene-2,2'-indoline] derivatives as potent inhibitors of peptidylarginine deiminase IV to treat rheumatoid arthritis

Peptidylarginine deiminase isoform 4 (PADI4) is a potential therapeutic target for treatment of rheumatoid arthritis. Auto-antibodies induced by the dysregulated catalysis of peptidylarginine into peptidylcitrulline by PADI4 can cause the onset and progression of rheumatoid arthritis. Herein, we report a novel class of spiro[chromene-2,2'-indoline] derivatives which were synthesized and optimized from a hit discovered by screening two libraries with 3760-members of natural products and derivatives for PADI4 inhibitors. In vitro, our derivatives were proved capable of potently inhibiting PADI4 and diminishing cellular citrullination; in vivo, the representative compound 7, 6,8-dimethoxy-1',3',3'-trimethylspiro[chromene-2,2'-indoline], effectively ameliorated the severity and pathologic progress of Collagen type II antibody/LPS induced rheumatoid arthritis in a mouse model. This work establishes compound 7 and the related potent compounds worthy of further study and development to treat rheumatoid arthritis, and validates PADI4 as a therapeutic target for this purpose.

Arginine; Citrullination; Citrulline; Inflammation; Peptidylarginine deiminase; Rheumatoid arthritis.