title: Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts, 01605, United States.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
authors.forename: Sangram
authors.initials: S
authors.lastname: Parelkar
authors.forename: Lynne
authors.initials: L
authors.lastname: Anguish
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coonrod
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
mesh_terms: D000578:Amidines / Q000737:chemistry*; D002712:Chlorides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000578:Amidines; D002712:Chlorides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013777:Tetrazoles; C045574:1H-tetrazole; D006867:Hydrolases; C019723:arginine deiminase