Effects of KP-496, a Novel Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors, on Contractions Induced by Various Agonists in the Guinea Pig Trachea

Autor: Takashi Maeda, Yoshiyuki Hiyama, Masakazu Ishimura, Masahiro Suda, Sayuri Kataoka
Rok vydání: 2006
Předmět:
Atropine
Cyclopropanes
Male
Indoles
Thromboxane
Indomethacin
Drug Evaluation
Preclinical
thromboxane A2
Acetates
Substance P
Pharmacology
Dinoprost
Receptors
Thromboxane A2
Prostaglandin H2
Leukotriene D4
Tosyl Compounds
Thromboxane A2
chemistry.chemical_compound
Benzoquinones
Immunology and Allergy
Zafirlukast
Sulfonamides
Leukotriene
biology
Prostaglandin D2
Tryptophan
General Medicine
respiratory system
Seratrodast
Trachea
Competitive antagonist
Quinolines
lipids (amino acids
peptides
and proteins)
Ketanserin
Powders
Histamine
Muscle Contraction
medicine.drug
lcsh:Immunologic diseases. Allergy
Serotonin
Prostaglandin Antagonists
Guinea Pigs
Phenylcarbamates
In Vitro Techniques
Sulfides
Pranlukast
Procaterol
medicine
Animals
Albuterol
Ketotifen
antagonist
Muscle
Smooth
asthma
Acetylcholine
anti-asthmatic drugs
chemistry
Chromones
Heptanoic Acids
15-Hydroxy-11 alpha
9 alpha-(epoxymethano)prosta-5
13-dienoic Acid
biology.protein
Leukotriene Antagonists
Carbachol
Thromboxane-A synthase
lcsh:RC581-607
Zdroj: Allergology International, Vol 55, Iss 4, Pp 403-410 (2006)
ISSN: 1323-8930
Popis: Background A dry powder inhaler of KP-496 is currently in clinical development in Japan as an antiasthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496. Methods The antagonistic activities of KP-496 for leukotriene (Lt) D 4 and thromboxane (TX) A 2 receptors were examined using the LTD4 - 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. Results 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 2 α-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. Conclusions 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.
Databáze: OpenAIRE
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