Development of novel leukotriene--based anti-asthma drugs: MK-886 and MK-571.

Abstract

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.

• Authors: R N Young
• Journal: Agents and actions. Supplements (Agents Actions Suppl) Vol. 34 Pg. 179-87 ( 1991) ISSN: 0379-0363 [Print] Switzerland
• PMID: 1793062 (Publication Type: Journal Article, Review)

Chemical References

• Indoles
• Leukotriene Antagonists
• Propionates
• Quinolines
• SRS-A
• MK-886
• verlukast

Topics

• Animals
• Asthma (drug therapy)
• Chemistry, Pharmaceutical
• Clinical Trials as Topic
• Humans
• Indoles (chemistry, therapeutic use)
• Leukotriene Antagonists
• Propionates (chemistry, therapeutic use)
• Quinolines (chemistry, therapeutic use)
• SRS-A (antagonists & inhibitors)
• Structure-Activity Relationship