Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitors: Synthesis, biological profile, and pharmacokinetics of L-739,010

被引:31
作者
Hamel, P
Riendeau, D
Brideau, C
Chan, CC
Desmarais, S
Delorme, D
Dube, D
Ducharme, Y
Ethier, D
Grimm, E
Falgueyret, JP
Guay, J
Jones, TR
Kwong, E
McAuliffe, M
McFarlane, CS
Piechuta, H
Roumi, M
Tagari, P
Young, RN
Girard, Y
机构
[1] MERCK FROSST CTR THERAPEUT RES,DEPT MED CHEM,POINTE CLAIRE,PQ H9R 4P8,CANADA
[2] MERCK FROSST CTR THERAPEUT RES,DEPT BIOCHEM,POINTE CLAIRE,PQ H9R 4P8,CANADA
[3] MERCK FROSST CTR THERAPEUT RES,DEPT PHARMACOL,POINTE CLAIRE,PQ H9R 4P8,CANADA
[4] MERCK FROSST CTR THERAPEUT RES,DEPT PHARMACEUT RES & DEV,POINTE CLAIRE,PQ H9R 4P8,CANADA
关键词
D O I
10.1021/jm970046b
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicycle derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC(50)s of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 mu g/kg/min, respectively, iv infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, respectively at 2.5 mu g/kg/min, iv infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in R-L and 76% in the decrease of C-dyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.
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页码:2866 / 2875
页数:10
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