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 po...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-04, Vol.37 (7), p.913-923
Main Authors: Lazer, Edward S, Miao, Clara K, Wong, Hin-Chor, Sorcek, Ronald, Spero, Denice M, Gilman, Alex, Pal, Kollol, Behnke, Mark, Graham, Anne G
Format: Article
Language:English
Subjects:
Arachidonic Acid - metabolism
Benzoxazoles - chemistry
Benzoxazoles - pharmacology
Chemistry
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Humans
In Vitro Techniques
Leukotriene Antagonists
Leukotrienes - biosynthesis
Neutrophils - drug effects
Neutrophils - metabolism
Organic chemistry
Preparations and properties
Stereoisomerism
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00033a008