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: Corey P Causey, Justin E Jones, Jessica L Slack, Daisuke Kamei, Larry E Jones, Venkataraman Subramanian, Bryan Knuckley, Pedram Ebrahimi, Alexander A Chumanevich, Yuan Luo, Hiroshi Hashimoto, Mamoru Sato, Lorne J Hofseth, Paul R Thompson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 19 Pg. 6919-35 (Oct 13 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21882827 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amidines
• Antineoplastic Agents
• N-alpha-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)ornithine amide
• N-alpha-(2-carboxyl)benzoyl-N5-(2-fluoro-1-iminoethyl)ornithine amide
• Doxorubicin
• Ornithine
• Hydrolases

Topics

• Amidines (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Biological Availability
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Crystallography, X-Ray
• Doxorubicin (pharmacology)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Humans
• Hydrolases (antagonists & inhibitors, chemistry)
• Kinetics
• Molecular Structure
• Ornithine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship