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

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 glycineextended precursors to the active amidated peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine alpha-monooxygenase ( PAM) and peptidylamidoglycolate lyase. We have demonstrated previously that 4- phenyl- 3butenoic 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 mechanismbased 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 antiinflammatory compounds.