title: 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.affiliation: Department of Pharmacology, Hoffmann-La Roche Inc., Nutley, New Jersey.
authors.forename: M
authors.initials: M
authors.lastname: O'Donnell
authors.forename: H J
authors.initials: HJ
authors.lastname: Crowley
authors.forename: B
authors.initials: B
authors.lastname: Yaremko
authors.forename: N
authors.initials: N
authors.lastname: O'Neill
authors.forename: A F
authors.initials: AF
authors.lastname: Welton
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D015289:Leukotrienes / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000378:metabolism / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D015289:Leukotrienes; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013844:Thiazoles; C071436:cinalukast