A new class of leukotriene biosynthesis inhibitor: the development of MK-0591.
The evolution of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy+ ++)indol-2-yl]- 2,2-dimethylpropanoic acid), 12, a potent, orally active leukotriene biosynthesis inhibitor is described. MK-0591 is currently undergoing clinical evaluation as a potential agent for the treatment of asthma and inflammatory bowel disease. It acts through a novel mechanism by a specific interaction with a membrane protein, 5-lipoxygenase activating protein (FLAP), which has been shown to be essential for LT synthesis in inflammatory cells. A brief comparison of its biological activity with that of its progenitors MK-886 and L-674,636 is described.
Prasit
P
P
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Belley
M
M
Blouin
M
M
Brideau
C
C
Chan
C
C
Charleson
S
S
Evans
J F
JF
Frenette
R
R
Gauthier
J Y
JY
Guay
J
J
D058927:5-Lipoxygenase-Activating Proteins; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D002352:Carrier Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C548592:ALOX5AP protein, human; C060893:MK-886; D002722:Chlorobenzenes; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; C078266:MK 0591