Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors.
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Amidines; Chlorides; Dose-Response Relationship, Drug; *Drug Design; Enzyme Inhibitors; Humans; Hydrolases; Isoenzymes; Molecular Structure; Structure-Activity Relationship; Tetrazoles
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiology of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isozyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isozyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isozymes. Importantly, one of the compounds, biphenyl tetrazole tert-butyl Cl-amidine (compound 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs.
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Citation: J Med Chem. 2015 Feb 12;58(3):1337-44. doi: 10.1021/jm501636x.Link to article on publisher's site
Subramanian, Venkataraman; Knight, Jason S.; Parelkar, Sangram; Anguish, Lynne; Coonrod, Scott A.; Kaplan, Mariana J.; and Thompson, Paul R., "Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors." (2015). Thompson Lab Publications. 5.