Study of arginine mimetic benzamidine urea derivatives as PAD4 inhibitors

Abstract

Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease, where antibodies are generated against citrullinated proteins. Citrullinated proteins are catalytic products of the Peptidyl Arginine Deiminase 4 (PAD4) enzyme. Since PAD4 acts on peptidyl arginine, a series of arginine mimetic compounds having 4-benzamidine urea scaffold were synthesized and evaluated for PAD4 inhibitory potential. These derivatives showed weak inhibitory activity. To understand the reason, docking studies were performed. Analysis of docking poses revealed that important binding interactions observed in the reported substrate were not exhibited by these synthesized compounds. These results suggest that 4-benzamidine urea derivatives known for their arginine mimetic property might not be useful as lead structures for development as PAD4 inhibitors.