- Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5- lipoxygenase inhibitor
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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-naphthol (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.
- Yatabe, Takumi,Kayakiri, Hiroshi,Kawai, Yoshio,Oku, Teruo,Tanaka, Hirokazu
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p. 1556 - 1565
(2007/10/03)
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- Quinolyl methoxy compounds, processes for preparation thereof and pharmaceutical composition comprising the same
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The invention relates to an anti-inflammatory or antiallergic composition containing a compound of the formula STR1 wherein A is STR2 R1 is aryl which may have cyano or carbamoyl, or heterocyclic group which may have lower alkyl, R2 is hydrogen or lower alkyl, R3 is lower alkyl, X is hydrogen, halogen, hydroxy or lower alkyl, m is an integer 1 or 2, and n is an integer 1 to 4, or pharmaceutically acceptable salts thereof.
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- Quinolyl methoxy compounds, processes for preparation thereof and pharmaceutical composition comprising the same
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The invention relates to a method of treating arteriosclerosis or pancreatitis comprising administering a compound of the formula: STR1 wherein A is STR2 R1 is quinolyl, R2 is hydrogen or lower alkyl, R3 is lower alkyl, X is hydrogen, halogen, hydroxy or lower alkyl, m is an integer 1 or 2, and n is an integer 1 to 4, or pharmaceutically acceptable salts thereof.
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