Title

The development of N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

10-13-2011

Document Type

Article

Subjects

Amidines; Antineoplastic Agents; Apoptosis; Biological Availability; Cell Differentiation; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Hydrolases; Kinetics; Molecular Structure; Ornithine; Structure-Activity Relationship

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

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-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(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.

DOI of Published Version

10.1021/jm2008985

Source

J Med Chem. 2011 Oct 13;54(19):6919-35. doi: 10.1021/jm2008985. Epub 2011 Sep 16. Link to article on publisher's site

Journal/Book/Conference Title

Journal of medicinal chemistry

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed