Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5-lipoxygenase inhibitor.
Chem Pharm Bull (Tokyo)
; 46(10): 1556-65, 1998 Oct.
Article
em En
| MEDLINE
| ID: mdl-9810693
ABSTRACT
A novel series of 2,2-dialkyl-5-(2-quinolylmethoxy)-1,2,3, 4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC50s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphtho l (FR110302, (+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC50 4.9 nM) and in humans (IC50 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Inibidores de Lipoxigenase
/
Naftóis
Limite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Chem Pharm Bull (Tokyo)
Ano de publicação:
1998
Tipo de documento:
Article