1,4-Dihydronaphthoquinones as water-soluble inhibitors of 5-lipoxygenase.
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.
Schaub
R G
RG
Research Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Yamashita
A
A
Bach
M K
MK
White
G J
GJ
Toy
A
A
Ghazal
N B
NB
Simmons
C A
CA
Burdick
M D
MD
Brashler
J R
JR
Holm
M S
MS
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
D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D001091:Arachidonate Lipoxygenases