Protein arginine deiminase (PADs), members of the amidinotransferase super family of enzymes, are responsible for an important posttranslational modification of arginine called citrullination or deamination. This once obscure modification is involved in the onset and progression of many autoimmune diseases such as Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Lupus, Ulcerative Colitis (UC), and in some forms of cancer. Among the five human PADs (PAD1, 2, 3, 4, and PAD6), it is unclear which of PAD isozymes contributes to disease pathogenesis. In our study towards identifying potent, selective and bioavailable PAD inhibitors as useful chemical probes to elucidate the specific roles of each isozymes, here we describe triazole analogs as a suitable amide mimetic for the parent Cl-amidine. The synthezised triazole analogs of Cl-amidine are highly selective inhibitors of PAD3 relative to other PAD isozymes. Herein we show percent inhibition studies carried out for all of the synthesized molecules to measure efficacy. The most promising candidates from the inhibition study will be carried on to in cellulo studies to determine their efficacy.

Identification of 4-aryl-1H-1,2,3-triazoles as selective protein arginine deiminase 3 inhibitors

247th National Meeting (2014)

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