title: 1,4-Dihydronaphthoquinones as water-soluble inhibitors of 5-lipoxygenase.
abstract: The acetate derivatives of 1,4-dihydronaphthoquinones showed significant inhibition of 5-lipoxygenase. Among them, 1-acetyl-2-n-butyl-4-methoxy-naphthalene and 1-acetyl-2, 3-diethyl- 4- methoxy-naphthalene were found to be the best inhibitors. A series of HCl salts of the amino acid esters and other derivatives of the two parent molecules, 1-hydroxy-2-n-butyl-4-methoxy-naphthalene and 1-hydroxy-2, 3-diethyl-4-methoxynaphthalene, were synthesized as water-soluble potential inhibitors of 5-lipoxygenase to improve the formulation characteristics of this class of compounds. The derivatives were evaluated for leukotriene (LT) C4/D4 and LTB4 inhibitory activity. The HCl salts of the L-valine esters from the two parent molecules exhibited the best potency for inhibition of LTC4/D4 (IC50 0.11-0.90 microM) in ionophore A23187-stimulated rat mononuclear cells and of LTB4 in A23187-stimulated rat blood (55.5-79.2% inhibition) following a single oral dose of 50 mg/kg.
authors.affiliation: Research Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: R G
authors.initials: RG
authors.lastname: Schaub
authors.forename: A
authors.initials: A
authors.lastname: Yamashita
authors.forename: M K
authors.initials: MK
authors.lastname: Bach
authors.forename: G J
authors.initials: GJ
authors.lastname: White
authors.forename: A
authors.initials: A
authors.lastname: Toy
authors.forename: N B
authors.initials: NB
authors.lastname: Ghazal
authors.forename: C A
authors.initials: CA
authors.lastname: Simmons
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: J R
authors.initials: JR
authors.lastname: Brashler
authors.forename: M S
authors.initials: MS
authors.lastname: Holm
mesh_terms: D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D016859:Lipoxygenase Inhibitors; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility
chemical_list: D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D001091:Arachidonate Lipoxygenases