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.