1,4-Dihydronaphthoquinones, hydroindoloquinones, benzofurans, and benzothiophenes as inhibitors of 5-lipoxygenase. Synthesis and structure-activity studies.
A series of substituted 1,4-dihydronaphthoquinones, hydroindoloquinones, benzofuran-4,7-dihydroquinones, and benzothiophene-4,7-dihydroquinones were synthesized and evaluated for inhibitory activity against 5-lipoxygenase. These compounds were found to be active in vitro for LTC4/D4 inhibition with the potencies (IC50's) ranging from 0.2 to 85 microM. Active 1,4-dihydronaphthoquinone acetates (IC50 less than 20 microM) were evaluated in an ex vivo LTB4 inhibition assay. The acetates of 1,4-dihydronaphthoquinones containing the alkyl substituent(s) (2-n-butyl, 11, and 2,3-diethyl, 15) exhibited the best activity in LTC4/D4 inhibition (IC50 = 0.2-0.4 microM, in vitro) as well as in LTB4 inhibition (60-75% inhibition).
Yamashita
A
A
Research Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Schaub
R G
RG
Bach
M K
MK
White
G J
GJ
Toy
A
A
Ghazal
N B
NB
Burdick
M D
MD
Brashler
J R
JR
Holm
M S
MS
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones / Q000494:pharmacology*; D011809:Quinones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013189:SRS-A / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
D001572:Benzofurans; D004791:Enzyme Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D011809:Quinones; D013189:SRS-A; D013876:Thiophenes; D007975:Leukotriene B4; D001091:Arachidonate Lipoxygenases