SC 57461A

Product NameSC 57461A
CAS423169-68-0
MFC20H25NO3.ClH
MW363.882
EINECS
MOL File423169-68-0.mol

Chemical Properties

Melting point	163-165°C
storage temp.	Desiccate at +4°C
solubility	DMSO: >5mg/mL
form	powder
color	white to off-white
InChI	1S/C20H25NO3.ClH/c1-21(14-12-20(22)23)13-5-15-24-19-10-8-18(9-11-19)16-17-6-3-2-4-7-17;/h2-4,6-11H,5,12-16H2,1H3,(H,22,23);1H
InChIKey	SBBJJLDNKNNWFJ-UHFFFAOYSA-N
SMILES	Cl.CN(CCCOc1ccc(Cc2ccccc2)cc1)CCC(O)=O

Safety Information

Hazard Codes	Xn
Risk Statements	22-36/37/38
Safety Statements	26
WGK Germany	3
Storage Class	11 - Combustible Solids
Hazard Classifications	Acute Tox. 4 Oral Eye Irrit. 2 Skin Irrit. 2

Usage And Synthesis

Description

Leukotriene A₄ (LTA₄) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that both catalyzes the synthesis of LTB₄ from LTA4 and cleaves the chemotactic peptide Pro-Gly-Pro. SC-57461A is a potent, orally active inhibitor of LTA₄ hydrolase that blocks ionophore-stimulated LTB₄ synthesis in whole blood (IC₅₀ = 49 nM). It blocks both the hydrolase and aminopeptidase activity in vitro. SC-57461A is without effect against other enzymes of the arachidonic acid cascade, including 5-lipoxygenase, LTC₄ synthase, COX-1, and COX-2. In a rat model of ionophore-induced peritoneal eicosanoid production, SC-57461A inhibits LTB₄ biosynthesis without affecting LTC₄ or 6-keto prostaglandin F_1α production . Oral or topical pretreatment with SC-57461A before challenge with arachidonic acid blocks ear edema in mice.

Chemical Properties

White Solid

Uses

A potent and selective orally active leukotriene A4 hydrolase inhibitor.

Uses

SC 57461A is a potent and selective inhibitor of LTA4.

Biological Activity

Potent and selective inhibitor of LTA 4 hydrolase. Does not inhibit other enzymes of the arachidonic acid cascade including COX-1, COX-2, LTC 4 synthase and 5-lipoxygenase. Potently inhibits LTB 4 production in whole blood (IC 50 = 49 nM). Orally active.

in vivo

SC-57461A also shows excellent potency in the mouse ex vivo assay, inhibiting the production of LTB4 with an ED₅₀=0.2 mg/kg and an ED₉₀=1 mg/kg. SC-57461A also inhibits the production of LTB4 in the rat peritoneal model with an ED₅₀=1 mg/kg^[2]. SC-57461A is a potent, selective, and competitive inhibitor of LTA4 hydrolase with excellent activity in whole animals. SC-57461A demonstrates good oral activity in both the mouse and the rat^[3].

Animal Model:	Fasted CD rats^[3]
Dosage:	0.01, 0.1, 1, and 10 mg/kg
Administration:	Orally administered
Result:	The ED₅₀ values were 0.2 mg/kg at 1.0 h and 0.8 mg/kg at 3.0 h. A single dose of 10 mg/kg blocked LTB4 production 79% at 6 h, 67% at 18 h, and 44% at 24 h.

References

[1] THOMAS D. PENNING. Synthesis of Potent Leukotriene A4 Hydrolase Inhibitors. Identification of 3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid[J]. Journal of Medicinal Chemistry, 2002, 45 16: 3482-3490. DOI: 10.1021/jm0200916
[2] KACHUR J, ASKONAS L J, VILLANI-PRICE D, et al. 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.[J]. The Journal of Pharmacology and Experimental Therapeutics, 2002, 20 1: 0. DOI: 10.1124/jpet.300.2.583
[3] KACHUR J, ASKONAS L J, VILLANI-PRICE D, et al. 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.[J]. The Journal of Pharmacology and Experimental Therapeutics, 2002, 20 1: 0. DOI: 10.1124/jpet.300.2.583

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