Anti-Inflammatory Effects of 4-Phenyl-3-butenoic Acid and 5-(Acetylamino)-4-oxo-6-phenyl-2-hexenoic Acid Methyl Ester, Potential Inhibitors of Neuropeptide Bioactivation

• Published in: The Journal of pharmacology and experimental therapeutics 2007-03, Vol.320 (3), p.1171-1177
• Main Authors: Bauer, John D, Sunman, Jeffrey A, Foster, Michael S, Thompson, Jeremy R, Ogonowski, Alison A, Cutler, Stephen J, May, Sheldon W, Pollock, Stanley H
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Caproates - chemistry; Caproates - pharmacology; Caproates - therapeutic use; Cyclooxygenase 1 - blood; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - blood; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Edema - drug therapy; Edema - metabolism; Esters - chemistry; Esters - pharmacology; Esters - therapeutic use; Fatty Acids, Monounsaturated - chemistry; Fatty Acids, Monounsaturated - pharmacology; Fatty Acids, Monounsaturated - therapeutic use; Group II Phospholipases A2; Humans; In Vitro Techniques; Male; Molecular Structure; Neuropeptides - metabolism; Phospholipases A - metabolism; Rats; Rats, Sprague-Dawley; Sciatic Nerve - metabolism; Substance P - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.106.110940

Substance P (SP) and calcitonin gene-related peptide (CGRP) are well established mediators of inflammation. Therefore, inhibition of the biosynthesis of these neuropeptides is an attractive potential strategy for pharmacological intervention against a number of inflammatory diseases. The final step in the biosynthesis of SP and CGRP is the conversion of their glycine-extended precursors to the active amidated peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine α-monooxygenase (PAM) and peptidylamidoglycolate lyase. We have demonstrated previously that 4-phenyl-3-butenoic acid (PBA) is a PAM inhibitor, and we have also shown that in vivo inhibition of serum PAM by PBA correlates with this compound's ability to inhibit carrageenan-induced edema in the rat. Here we demonstrate the ability of PBA to inhibit all three phases of adjuvant-induced polyarthritis (AIP) in rats; this represents the first time that an amidation inhibitor has been shown to be active in a model of chronic inflammation. We recently introduced 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid (AOPHA) as one of a new series of mechanism-based amidation inhibitors. We now report for the first time that AOPHA and its methyl ester (AOPHA-Me) are active inhibitors of serum PAM in vivo, and we show that AOPHA-Me correspondingly inhibits carrageenan-induced edema in rats in a dose-dependent manner. Neither PBA nor AOPHA-Me exhibits significant cyclooxygenase (COX) inhibition in vitro; thus, the anti-inflammatory activities of PBA and AOPHA-Me are apparently not a consequence of COX inhibition. We discuss possible pharmacological mechanisms that may account for the activities of these new anti-inflammatory compounds.