Benzoxazolamines and benzothiazolamines: potent, enantioselective inhibitors of leukotriene biosynthesis with a novel mechanism of action.
A series of benzoxazolamine and benzothiazolamine analogs that inhibit leukotriene (LT) biosynthesis are described. The initial lead, (S)-N-(benzothiazol-2- yl)phenylalanine ethyl ester (5a), was discovered in a screening program for inhibition of Ca-ionophore-A23187-induced LTB4 release in human polymorphonuclear leukocytes (IC50 0.23 microM). Through structural modification, it was determined that hydrophobic substituents in the 5-position and replacement of the phenyl ring of phenylalanine with a cyclohexyl group greatly enhance potency. Several ester bioisosteres that retain potency and enantiomeric selectivity are described. Lead optimization culminated in (S)-N-[2-cyclohexyl-1-(2-pyridinyl)ethyl]-5-methyl-2-benzoxazolamine+ ++ (43b), IC50 0.001 microM. The compounds described are not inhibitors of 5-lipoxygenase but, rather, act at the level of arachidonic acid release.
Lazer
E S
ES
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Incorporated, Ridgefield, Connecticut 06877.
Miao
C K
CK
Wong
H C
HC
Sorcek
R
R
Spero
D M
DM
Gilman
A
A
Pal
K
K
Behnke
M
M
Graham
A G
AG
Watrous
J M
JM
D016718:Arachidonic Acid / Q000378:metabolism; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D001583:Benzoxazoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D013844:Thiazoles; D016718:Arachidonic Acid