Pharmacological characterization of SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl), a potent and selective inhibitor of leukotriene A(4) hydrolase I: in vitro studies

Leukotriene (LT) B(4) is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB(4) production, LTA(4) hydrolase represents an attractive target for therapeutic agents that interfere with LTB(4) production. In the present study we evaluated a chemically novel compound designated SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) as an inhibitor of LTA(4) hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA(4) hydrolase when either LTA(4) (IC(50) = 2.5 nM, K(i) = 23 nM) or peptide substrates (IC(50) = 27 nM) are used. In human whole blood, the IC(50) for calcium ionophore-induced LTB(4) production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B(2) was not affected. SC-57461A was also active in several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA(4) hydrolase.