An improved synthesis of haloaceteamidine-based inactivators of protein arginine deiminase 4 (PAD4)

Tetrahedron Lett. 2008 Jul 7;49(28):4383-4385. doi: 10.1016/j.tetlet.2008.05.021.


Protein arginine deiminase 4 (PAD4) is an enzyme that hydrolyzes peptidyl arginine residues to form citrulline and ammonia. This enzyme has been implicated in several disease states, e.g. rheumatoid arthritis, and therefore represents a unique target for the development of a novel therapeutic. A solution-phase synthesis of Cl-amidine, the most potent PAD4 inactivator described to date, has been developed. This synthesis proceeds in 80% yield over 4 steps at a significantly (12-fold) lower cost.