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.
Askonas
Leslie J
LJ
Pharmacia Research and Development, Skokie, Illinois, USA. leslie.j.askonas@pharmacia.com
Kachur
James F
JF
Villani-Price
Doreen
D
Liang
Chi-Dean D
CD
Russell
Mark A
MA
Smith
Walter G
WG
D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015777:Eicosanoids / Q000096:biosynthesis / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D017572:Leukotriene A4 / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008253:Macaca mulatta; D051379:Mice; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity; D013379:Substrate Specificity; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D015777:Eicosanoids; D004791:Enzyme Inhibitors; D007476:Ionophores; D017572:Leukotriene A4; D020024:Leukotriene Antagonists; D011994:Recombinant Proteins; C104311:SC 57461; D015091:beta-Alanine; D016718:Arachidonic Acid; D004851:Epoxide Hydrolases; D000626:Aminopeptidases; C043134:leukotriene A4 hydrolase