Protein arginine deiminases (PADs), members of the amidinotransferase superfamily ofenzymes, are responsible for an important posttranslational modification of argininecalled protein citrullination or deimination. This once obscure modification is involvedin the onset and progression of many autoimmune diseases such as Rheumatoid Arthritis(RA), Multiple Sclerosis (MS), Lupus, Ulcerative Colitis (UC), and in some forms ofcancer. Among the five human PADs (PAD1, 2, 3, 4 and PAD6), it is unclear which ofthe PAD isozymes contributes to disease pathogenesis. Towards the identification ofpotent, selective, and bioavailable PAD inhibitors as useful chemical probes to elucidatethe specific roles of each isozyme, we describe tetrazole based analogs of Cl-amidine as PADinhibitors:  The tetrazole  serves as suitable amide bioisostere for the parent Cl-amidine.These compounds are highly potent and some of the analogs show excellentselectivity towards particular isozymes. These compounds also possess enhancedpharmacokinetic properties. Importantly, one of the compounds, biphenyl tetrazoletert butyl Cl-amidine exhibits significant cell killing in the PAD4 expressing, osteosarcomabone marrow (U2OS) cell line. These tetrazole based analogs represent an important step inour efforts to develop stable, bioavailable and highly selective inhibitors for the PADs.

Design, synthesis, and biological evaluation of tetrazole analogs as protein arginine deiminase inhibitors

247th National Meeting (2014)

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