Quinolines as potent 5-lipoxygenase inhibitors: synthesis and biological profile of L-746,530.
Leukotriene biosynthesis inhibitors have potential as new therapeutic agents for asthma and inflammatory diseases. A series of novel substituted 2-cyanoquinolines have been synthesized and the structure activity relationships were evaluated with respect to their ability to inhibit the formation of leukotrienes via the 5-lipoxygenase enzyme. [1S,5R]-2-Cyano-4-(3-furyl)-7-¿3-fluoro-5-[3-(3 alpha-hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)]phenoxymethyl ¿quinoline (L-746,530) 3 represents a distinct class of inhibitors and possesses in vitro and in vivo potency comparable or superior to naphthalenic analog (L-739,010) 2.
Dubé
D
D
Merck Frosst Centre For Therapeutic Research, Québec, Canada.
Blouin
M
M
Brideau
C
C
Chan
C C
CC
Desmarais
S
S
Ethier
D
D
Falgueyret
J P
JP
Friesen
R W
RW
Girard
M
M
Girard
Y
Y
Guay
J
J
Riendeau
D
D
Tagari
P
P
Young
R N
RN
D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D006801:Humans; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D001643:Bridged Bicyclo Compounds; C100578:L 746530; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D011804:Quinolines; D011994:Recombinant Proteins; D007975:Leukotriene B4