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 II: in vivo studies.
Leukotriene (LT) A(4) hydrolase is a dual function enzyme that is essential for the conversion of LTA(4) to LTB(4) and also possesses an aminopeptidase activity. SC-57461A (3-[methyl[3-[4-phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA(4) hydrolase (epoxide hydrolase and aminopeptidase activities, K(i) values = 23 and 27 nM, respectively) as well as calcium ionophore-induced LTB(4) production in human whole blood (IC(50) = 49 nM). In the present study, we investigated its action in several animal models. Oral activity was evident from the ability of the compound to inhibit mouse ex vivo calcium ionophore-stimulated blood LTB(4) production with ED(50) values at 1.0 and 3.0 h of 0.2 and 0.8 mg/kg, respectively. A single oral dose of 10 mg/kg SC-57461A blocked mouse ex vivo LTB(4) production 67% at 18 h and 44% at 24 h, suggesting a long pharmacodynamic half-life. In a rat model of ionophore-induced peritoneal eicosanoid production, SC-57461 inhibited LTB(4) production in a dose-dependent manner (ED(50) = 0.3-1 mg/kg) without affecting LTC(4) or 6-keto-prostaglandin F(1alpha) production. Oral pretreatment with SC-57461 in a rat reversed passive dermal Arthus model blocked LTB(4) production with an ED(90) value of 3 to 10 mg/kg, demonstrating good penetration of drug into skin. Plasma level of intact SC-57461 (3 h after oral gavage dosing with 3 mg/kg) was 0.4 microg/ml, which corresponds to >80% inhibition of dermal LTB(4) production. Oral or topical pretreatment with SC-57461A 1 h before challenge with arachidonic acid blocked ear edema in the mouse. SC-57461A is a competitive, selective, and orally active inhibitor of LTA(4) hydrolase in vivo, making it useful to explore the contribution of LTB(4) to a number of inflammatory diseases.
Kachur
James F
JF
Pharmacia Research and Development, Skokie, Illinois 60077, USA. james.f.kachur@pharmacia.com
Askonas
Leslie J
LJ
Villani-Price
Doreen
D
Ghoreishi-Haack
Nayereh
N
Won-Kim
Suzanne
S
Liang
Chi-Dean D
CD
Russell
Mark A
MA
Smith
Walter G
WG
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D001183:Arthus Reaction / Q000473:pathology; D003872:Dermatitis / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D015777:Eicosanoids / Q000096:biosynthesis / Q000097:blood; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D017572:Leukotriene A4 / Q000096:biosynthesis*; D020024:Leukotriene Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*
D015777:Eicosanoids; D004791:Enzyme Inhibitors; D017572:Leukotriene A4; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; C104311:SC 57461; D015091:beta-Alanine; D004851:Epoxide Hydrolases; C063449:zileuton; C043134:leukotriene A4 hydrolase; D006918:Hydroxyurea