title: The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors.
abstract: Protein arginine deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These enzymes, there are five in humans (PADs 1-4 and 6), regulate gene transcription, cellular differentiation, and the innate immune response. Building on our successful generation of F- and Cl-amidine, which irreversibly inhibit all of the PADs, a structure-activity relationship was performed to develop second generation compounds with improved potency and selectivity. Incorporation of a carboxylate ortho to the backbone amide resulted in the identification of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine), as PAD inactivators with improved potency (up to 65-fold) and selectivity (up to 25-fold). Relative to F- and Cl-amidine, the compounds also show enhanced potency in cellulo. As such, these compounds will be versatile chemical probes of PAD function.
authors: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
authors: Corey P
authors: CP
authors: Causey
authors: Justin E
authors: JE
authors: Jones
authors: Jessica L
authors: JL
authors: Slack
authors: Daisuke
authors: D
authors: Kamei
authors: Larry E
authors: LE
authors: Jones
authors: Venkataraman
authors: V
authors: Subramanian
authors: Bryan
authors: B
authors: Knuckley
authors: Pedram
authors: P
authors: Ebrahimi
authors: Alexander A
authors: AA
authors: Chumanevich
authors: Yuan
authors: Y
authors: Luo
authors: Hiroshi
authors: H
authors: Hashimoto
authors: Mamoru
authors: M
authors: Sato
authors: Lorne J
authors: LJ
authors: Hofseth
authors: Paul R
authors: PR
authors: Thompson
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; C568520:N-alpha-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)ornithine amide; C568519:N-alpha-(2-carboxyl)benzoyl-N5-(2-fluoro-1-iminoethyl)ornithine amide; D004317:Doxorubicin; D009952:Ornithine; D006867:Hydrolases