To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.

The effects of (Z)-11-[(3-dimethylamino)propylidene]-6,11-dihydrodibenz[b.e.] oxepin-2-acetic acid monohydrochloride (KW-4679), an orally active antiallergic drug, on the production of platelet-activating factor (PAF), leukotriene (LT) and thromboxane (TX) induced by Ca²⁺ ionophore A23187 were examined. KW-4679 at 10 μM reduced the amount of cell-associated PAF by 52.8% in human polymorphonuclear leukocytes (PMNs). KW-4679 (1–100 μM) also inhibited the release of both LTB₄ and TXB₂, a stable metabolite of TXA₂, by human PMNs in a concentration-dependent manner, but did not influence the release of β-glucuronidase. The 50% inhibitory concentration (IC₅₀) values for LTB₄ and TXB₂ release were 5.9 and 6.0 μM, respectively. In guinea pig eosinophils, KW-4679 inhibited the release of peptide LTs at a concentration higher than 10 μM (IC₅₀ = 66.9 μM). KW-4679 failed to inhibit PAF acetyltransferase, 5-lipoxygenase and TX synthase, but inhibited the arachidonic acid rlease by human PMNs in a concentration-dependent manner at a similar concentration as that inhibiting production or release of lipid mediators (IC₅₀ =19.5 μM). These results indicate that KW-4679 suppresses LTs and TX release and PAF formation by reducing arachidonic acid release from phospholipids, probably through interference with phospholipase A₂. The inhibitory action of KW-4679 on PAF, LT and TX production is a beneficial effect of an antiallergic drug.

Pseudomonas methanica KY4634 was found to produce 5-lipoxygenase inhibitor designated KF8940, MY12-62a and MY12-62c. The inhibitors were purified by solvent extraction, silica gel column chromatography, reversed-phase low pressure liquid chromatography and crystallization. The chemical structures of KF8940, MY12-62a and MY12-62c were determined to be 2-n-heptyl-4-hydroxyquinoline-N-oxide, 2-n-heptyl-4-hydroxyquinoline and 3-n-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diore, respectively, on the basis of their physico-chemical properties. Among them, KF8940 was the most potent inhibitor. The compound inhibited 5-lipoxygenase of rat basophilic leukemia cells in a dose-dependent manner and the half maximal inhibitory concentration (IC,0) was 1.5 x 10 M. At this concentration, KF8940 did not inhibit bovine platelet 12-lipoxygenase and cyclooxygenase, and the IC,,0 values for these enzyme were 3.5 x 10-5 M and 1.7 x 10-4 M, respectively. The results indicated that KF8940 is a potent and selective inhibitor of 5-lipoxygenase. The IC50 value of MY12-62c for 5-lipoxygenase was 1.9 x 10 M and that of MY12-62a was 1.9 x 10-5M.Much attention has been focused on 5-lipoxygenase inhibitors as anti-asthmatic and anti-inflammatory agents since SAMUELSSON and co-workersl,2) showed that slow reacting substances of anaphylaxis (SRS-A), potent mediators generated during anaphylactic reaction, were oxidative products of arachidonate 5-lipoxygenase. The enzyme is mainly distributed in leukocytes3) and catalizes the oxygenation of arachidonic acid at C-5 position to produce 5-HPETE. The product can be either reduced enzymatically to its hydroxy derivative, 5-HETE, or transformed to the peptide LTs and LTB4. LTB4 was proposed to be implicated in inflammatory reactions because of its potent chemotactic activity4).Many compounds have recently been reported as 5-lipoxygenase inhibitors5-9) and some of them exhibited anti-asthmatic activities10,11). In the course of screening for lipoxygenase inhibitors from microbial origin, we found that Pseudomonas methanica KY4634 produced potent 5-lipoxygenase inhibitors. The compounds, designated KF8940, MY12-62a and MY12-62c, were isolated from the culture broth and their structures were determined. Among them, KF8940, 2-n-heptyl-4-hydroxyquinoline-N-oxide, was a potent and selective inhibitor of the enzyme. This manuscript describes the fermentation, isolation and purification, structural identification, and some biological properties of the inhibitors.

We investigated the effects of KW-4679, an antiallergic drug, on the development of bronchial hyperresponsiveness, airway inflammation and early and late asthmatic responses following aerosol antigen challenge in guinea pigs actively sensitized by the inhalation of aerosolized ovalbumin. Pretreatment with KW-4679 (10 mg/kg, p.o.) 1 h before antigen challenge prevented the development of bronchial hyperresponsiveness to inhaled methacholine. Examination of the bronchoalveolar lavage fluid 24 h after antigen challenge revealed the inhibitory effect of KW-4679 on the infiltration of eosinophils into the airway. Treatment with KW-4679 significantly inhibited both the immediate and late asthmatic responses. These results indicate that KW-4679 could be useful in the treatment of allergic diseases such as bronchial asthma.

A series of novel xanthine-based tricyclic heterocycles in 1H-imidazo[4,5-c]quinolin-4(5H)-ones was designed, synthesized, and tested as potential active bronchodilators. Inhibition of the Schulz-Dale (SD) reaction-induced contraction in trachea and inhibition of antigen inhalation-induced bronchospasm in passively sensitized guinea pigs served as primary in vitro and in vivo assays, respectively. Simultaneous measurement of acute lethal toxicity (minimum lethal dose; MLD, po) in mice allowed determination of a safety margin. The bronchodilatory activity of these heterocycles was considerably varied with the nature of substituents at the 5-position. The most active substituents at the 2- and 5-positions and on the aromatic ring were found to be hydrogen, n-butyl, and hydrogen, respectively. There was a bulk tolerance for lipophilic substituents at the 1-position. 5-Butyl-substituted compounds appeared to be less toxic than theophylline on the basis of MLD data. Thus 5-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4(5H)-one (10) (IC50 value of the SD assay = 0.25 microM, MLD > 300 mg/kg) was selected for further studies. Compound 10 (KF15570) reduced bronchoconstriction produced by antigen (Konzett-Rössler preparation in anesthetized guinea pigs, ED50 = 0.42 mg/kg, iv) more effectively than aminophylline (ethylenediamine salt of theophylline, ED50 = 7.8 mg/kg, iv) but had fewer side effects on the heart and CNS than theophylline. Compound 10 and its derivatives showed weak adenosine antagonism and phosphodiesterase (PDE) inhibition which could not account for their potent bronchodilation. Although their precise mechanism of action remains unclear, this series of novel tricyclic heterocycles represents a new class of bronchodilator.