Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors:  Synthesis, Biological Profile, and Pharmacokinetics of L-739,010

Abstract

Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo 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 (IC50S 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 microgram/kg/min, respectively, i.v. 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 micrograms/kg/min, i.v. infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease of Cdyn, 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.

Monitoring eicosanoid biosynthesis via lipoxygenase and cyclooxygenase pathways in human whole blood by single HPLC run

“…The results of IC 50 value determination of standard inhibitors of eicosanoid biosynthesis (Table 5) are consistent with literature data obtained in comparable test systems [17,[29][30][31]. However, when other cellular systems or even enriched enzyme preparations were used as test medium quite different results were obtained.…”

The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B4 in a novel human whole blood assay

“…RS14203 (Wilhelm & Fatheree, 1994), RP73401 (Souness et al, 1995), T-440 (Kaminuma et al, 1996), R-and S-rolipram, SB207499 (Christensen et al, 1998), CDP840 (Hughes et al, 1996), CT1731 (Hughes et al, 1996), Trequinsin, L-739,010 (Hamel et al, 1997), MF-tricyclic (selective cyclo-oxygenase-2 (COX-2) inhibitor) (Oshima et al, 1996) Figure 1 shows the time course of TNF-a and PGE 2 production after LPS-stimulation of whole blood. During the incubation period, a sharp rise in TNF-a levels was observed from 2 h (2.70+0.76 ng ml 71 ) to 4 h (15.59+3.61 ng ml 71 ) and peaked at 8 h (22.92+4.77 ng ml 71 ).…”

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

“…Such compounds are however, relatively non-selective and may interfere with a number of other cellular reactions. 3 Competitive inhibitors of the 5-lipoxygenase, which are based on thiopyranoindole and methoxyalkyl thiazole structures, and are more selective and may act as reversible non-redox inhibitors of 5-lipoxygenase [24,93].…”