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

• Published in: Journal of medicinal chemistry Vol. 40; no. 18; pp. 2866 - 2875
• Main Authors: Hamel, Pierre, Riendeau, Denis, Brideau, Christine, Chan, Chi-Chung, Desmarais, Sylvie, Delorme, Daniel, Dubé, Daniel, Ducharme, Yves, Ethier, Diane, Grimm, Erich, Falgueyret, Jean-Pierre, Guay, Jocelyne, Jones, Tom R, Kwong, Elizabeth, McFarlane, Cyril S, Piechuta, Hanna, Roumi, Marie, Tagari, Philip, Young, Robert N, Girard, Yves
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.08.1997; Amer Chemical Soc
• Subjects: Animals; Ascaris; Biological and medical sciences; Biological Availability; Bronchodilator Agents - chemical synthesis; Bronchodilator Agents - chemistry; Bronchodilator Agents - pharmacology; Chemistry, Medicinal; Dogs; Dyspnea - drug therapy; Humans; Inflammation; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - pharmacokinetics; Lipoxygenase Inhibitors - pharmacology; Magnetic Resonance Spectroscopy; Male; Medical sciences; Molecular Conformation; Molecular Structure; Naphthalenes - chemical synthesis; Naphthalenes - pharmacokinetics; Naphthalenes - pharmacology; Nematode Infections - physiopathology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyridines; Rats; Recombinant Proteins - antagonists & inhibitors; Respiratory system; Saimiri; Science & Technology; Sheep; Spodoptera; Transfection; MICROSOMAL METABOLISM; MK-0591; ANTAGONIST; ZILEUTON; PROTEIN; LEUKOTRIENE BIOSYNTHESIS; BRONCHOCONSTRICTION; INDUCED AIRWAY RESPONSES; ALLERGEN; ASTHMATIC SUBJECTS; Nitrile; Enzyme; Nitrogen heterocycle; Antiinflammatory agent; Furan derivatives; Oral administration; Enzyme inhibitor; Bioavailability; Antiasthma agent; Oxygen heterocycle; In vitro; Naphthalene derivatives; Pyridine derivatives; Acetal; In vivo; Structure activity relation; Hydrochlorides; Animal; Arachidonate 5-lipoxygenase; Bicyclic compound; Oxidoreductases; Pharmacokinetics; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970046b

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 μg/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 μg/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.