SUBSTITUTED (PYRIDYLMETHOXY)NAPHTHALENES AS POTENT AND ORALLY-ACTIVE 5-LIPOXYGENASE INHIBITORS - SYNTHESIS, BIOLOGICAL PROFILE, AND PHARMACOKINETICS OF L-739,010

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 tet rahydropyranyl counterparts but were not well orally absorbed. Replace ment of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, fury l)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]met hoxy]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 orall y 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 blo od LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 mu g/kg/min, respective ly, 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 conscio us sheep (50% and >85% inhibition in early and late phases, respective ly at 2.5 mu g/kg/min, iv infusion) and, more particularly in the cons cious antigen sensitive squirrel monkey model (53% inhibition of the i ncrease 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, res pectively, in methocel suspension). Based on its overall biological pr ofile, compound 3g has been selected for preclinical animal toxicity s tudies.