montelukast and seratrodast

Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Benzoquinones; Biomarkers; Cyclopropanes; Heptanoic Acids; Humans; Lung; Mice; Quinolines; Receptors, Eicosanoid; Sulfides

KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction.. Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated.. KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge.. KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetates; Administration, Inhalation; Administration, Oral; Airway Obstruction; Animals; Anti-Asthmatic Agents; Benzoates; Benzoquinones; Bronchoconstriction; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Heptanoic Acids; Leukotriene Antagonists; Leukotriene D4; Lung; Male; Membrane Proteins; Ovalbumin; Prostaglandin Antagonists; Quinolines; Receptors, Leukotriene; Receptors, Thromboxane A2, Prostaglandin H2; Respiratory Hypersensitivity; Sulfides; Thiazoles; Time Factors

A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496.. The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea.. KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea.. These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetates; Acetylcholine; Albuterol; Animals; Atropine; Benzoquinones; Carbachol; Chromones; Cyclopropanes; Dinoprost; Drug Evaluation, Preclinical; Guinea Pigs; Heptanoic Acids; Histamine; In Vitro Techniques; Indoles; Indomethacin; Ketanserin; Ketotifen; Leukotriene Antagonists; Leukotriene D4; Male; Muscle Contraction; Muscle, Smooth; Phenylcarbamates; Powders; Procaterol; Prostaglandin Antagonists; Prostaglandin D2; Quinolines; Receptors, Thromboxane A2, Prostaglandin H2; Serotonin; Substance P; Sulfides; Sulfonamides; Tosyl Compounds; Trachea; Tryptophan