Pharmacologic actions of Ro 24-5913, a novel antagonist of leukotriene D4.

Abstract

Ro 24-5913, (E)-4-[3-[2-(4-cyclobutyl-2- thiazolyl)ethenyl]phenylamino]-2,2-diethyl-4-oxobutanoic acid, has been identified as a chemically unique, potent and selective LTD4 antagonist. In vitro, Ro 24-5913 competes with [3H]LTD4 for its binding site on guinea pig lung membranes with an IC50 of 6.4 +/- 2.2 nM. In isolated guinea pig tracheal smooth muscle, Ro 24-5913 produces concentration-dependent rightward shifts of LTD4-induced contraction curves (pA2 value of 9.6 +/- 0.2). The slope of the Schild plot is not significantly different from 1, indicating that the antagonism is of a competitive nature. In the human bronchus, Ro 24-5913 is an effective antagonist of LTD4-induced contractions (pKB of 9.3 +/- 0.1). In vivo, Ro 24-5913 dose-dependently inhibits LTD4-induced bronchoconstriction in guinea pigs by the i.v. (ID50 0.13 mg/kg), oral (ID50 0.12 mg/kg) and aerosol (IC50 0.008%) routes of administration. This in vivo activity is specific as evidenced by the inability of Ro 24-5913 to inhibit bronchoconstriction induced by LTB4, PAF or histamine. In comparison with other LTD4 antagonists evaluated in this guinea pig model, Ro 24-5913 is markedly superior in terms of oral potency, bioavailability and oral duration of action. Ro 24-5913 also blocks allergic bronchospasm mediated by endogenously generated leukotrienes in guinea pigs; the potency and duration of action is nearly equivalent to that seen as an antagonist of bronchoconstrictions produced by exogenous LTD4. In summary, Ro 24-5913 is representative of a novel chemical class of LTD4 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: M O'Donnell, H J Crowley, B Yaremko, N O'Neill, A F Welton
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 259 Issue 2 Pg. 751-8 (Nov 1991) ISSN: 0022-3565 [Print] United States
• PMID: 1658310 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Leukotrienes
• Receptors, Immunologic
• Receptors, Leukotriene
• SRS-A
• Thiazoles
• cinalukast

Topics

• Animals
• Bronchi (drug effects, physiology)
• Bronchoconstriction (drug effects)
• Guinea Pigs
• Humans
• Leukotrienes (pharmacology)
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects, physiology)
• Receptors, Immunologic (antagonists & inhibitors, metabolism)
• Receptors, Leukotriene
• SRS-A (metabolism, pharmacology)
• Thiazoles (metabolism, pharmacology)
• Trachea (drug effects, physiology)