Document Detail

Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor.
MedLine Citation:
PMID:  1330258     Owner:  NLM     Status:  MEDLINE    
MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2,2-dimethyl propanoic acid, previously L-686,708) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human and elicited rat polymorphonuclear leukocytes (PMNLs) (IC50 values 3.1 and 6.1 nM, respectively) and in human, squirrel monkey, and rat whole blood (IC50 values 510, 69, and 9 nM, respectively). MK-0591 had no effect on rat 5-lipoxygenase. MK-0591 has a high affinity for 5-lipoxygenase activating protein (FLAP) as evidenced by an IC50 value of 1.6 nM in a FLAP binding assay and inhibition of the photoaffinity labelling of FLAP by two different photoaffinity ligands. Inhibition of activation of 5-lipoxygenase was shown through inhibition of the translocation of the enzyme from the cytosol to the membrane in human PMNLs. MK-0591 was a potent inhibitor of LT biosynthesis in vivo, first, following ex vivo challenge of blood obtained from treated rats and squirrel monkeys, second, in a rat pleurisy model, and, third, as monitored by inhibition of the urinary excretion of LTE4 in antigen-challenged allergic sheep. Inhibition of antigen-induced bronchoconstriction by MK-0591 was observed in inbred rats pretreated with methysergide, Ascaris-challenged squirrel monkeys, and Ascaris-challenged sheep (early and late phase response). These results indicate that MK-0591 is a potent inhibitor of LT biosynthesis both in vitro and in vivo indicating that the compound will be suitable for assessing the role of leukotrienes in pathological situations.
C Brideau; C Chan; S Charleson; D Denis; J F Evans; A W Ford-Hutchinson; R Fortin; J W Gillard; J Guay; D Guévremont
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Canadian journal of physiology and pharmacology     Volume:  70     ISSN:  0008-4212     ISO Abbreviation:  Can. J. Physiol. Pharmacol.     Publication Date:  1992 Jun 
Date Detail:
Created Date:  1992-12-23     Completed Date:  1992-12-23     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  0372712     Medline TA:  Can J Physiol Pharmacol     Country:  CANADA    
Other Details:
Languages:  eng     Pagination:  799-807     Citation Subset:  IM    
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
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MeSH Terms
Administration, Oral
Antigens / administration & dosage
Arachidonate 5-Lipoxygenase / antagonists & inhibitors,  drug effects,  metabolism
Ascaris / immunology
Bronchoconstriction / drug effects
Carrier Proteins / metabolism,  pharmacology
Drug Interactions
Indoles / blood,  pharmacology*
Leukotriene B4 / biosynthesis*,  blood
Membrane Proteins / metabolism,  pharmacology
Quinolines / blood,  pharmacology*
Rats, Sprague-Dawley
Reg. No./Substance:
0/5-lipoxygenase-activating protein; 0/Antigens; 0/Carrier Proteins; 0/Indoles; 0/Membrane Proteins; 0/Quinolines; 136668-42-3/MK 0591; 71160-24-2/Leukotriene B4; EC 5-Lipoxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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