Development of novel leukotriene--based anti-asthma drugs: MK-886 and MK-571.
A potent, selective and orally active receptor antagonist of leukotriene D4, MK-571, was discovered and developed from a styrylquinoline lead structure based on a hypothetical model of the leukotriene D4 receptor. MK-571 blocks the action of LTD4 in animals and man, and is effective in a number of animal models of antigen-induced bronchoconstriction at plasma concentration at or below 2 micrograms/mL. MK-571 also blocks antigen-induced asthmatic responses in man. In addition a series of 2-indolealkanoic acids was discovered to be inhibitors of leukotriene biosynthesis. From this series, MK-886, a nanomolar inhibitor of leukotriene biosynthesis was developed. The mechanism of action of MK-886 has been found to be the inhibition of activation of the 5-lipoxygenase enzyme. This inhibition is mediated by interaction with a specific 18 kD protein termed 5-lipoxygenase activating protein (FLAP). MK-886 is an inhibitor of leukotriene biosynthesis and of antigen-induced bronchoconstriction in animal models and in asthmatic men.
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Merck Frosst Centre for Therapeutic Research, Quebec, Canada.
D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical; D002986:Clinical Trials as Topic; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use*; D020024:Leukotriene Antagonists; D011422:Propionates / Q000737:chemistry / Q000627:therapeutic use*; D011804:Quinolines / Q000737:chemistry / Q000627:therapeutic use*; D013189:SRS-A / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D002722:Chlorobenzenes
D007211:Indoles; D020024:Leukotriene Antagonists; D011422:Propionates; D011804:Quinolines; D013189:SRS-A; C060893:MK-886; D002722:Chlorobenzenes; C059141:verlukast