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

• Ishimura Masakazu

  Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd.

• Kataoka Sayuri

  Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd.

• Suda Masahiro

  Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd.

• Maeda Takashi

  Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd.

• Hiyama Yoshiyuki

  Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd.

Abstract

Background: 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.<br> Methods: The antagonistic activities of KP-496 for leukotriene (LT) D₄ and thromboxane (TX) A₂ 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.<br> Results: KP-496 produced parallel rightward shifts of the LTD₄ 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 LTD₄ and TXA₂ receptors with pA₂ values of 8.64 and 8.23, respectively. The LTD₄ antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA₂ antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D₂- and PGF_2α-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.<br> Conclusions: These results indicate that KP-496 is a selective dual antagonist for LTD₄ and TXA₂ receptors. LTD₄ and TXA₂ 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.<br>

Journal

• Allergology International

  Allergology International 55 (4), 403-410, 2006

  Japanese Society of Allergology

Keywords

• antagonist
• anti-asthmatic drugs
• asthma
• leukotriene D₄
• thromboxane A₂

Details

• CRID: 1390001204634561152
• NII Article ID: 130004476914
• NII Article ID: 10018643198
• NII Book ID: AA11091750
• DOI: 10.2332/allergolint.55.403
• COI: 1:CAS:528:DC%2BD2sXmsl2gtg%3D%3D
• ISSN: 14401592
• ISSN: 13238930
• PubMed: 17130683
• Web Site: http://api.elsevier.com/content/article/PII:S1323893015309965?httpAccept=text/xml
• Web Site: http://api.elsevier.com/content/article/PII:S1323893015309965?httpAccept=text/plain
• Web Site: https://search.jamas.or.jp/link/ui/2007174336
• Text Lang: en
• Data Source:
  • JaLC
  • Crossref
  • PubMed
  • CiNii Articles
• Abstract License Flag: Disallowed