title: Pharmacological profile of the novel, potent and selective peptide leukotriene antagonist (E)-2,2-diethyl-3'-[2-[2-(4-isopropyl)thiazolyl]ethenyl]succinanilic acid.
abstract: In this report, the in vitro and in vivo pharmacological profile of MCI-826 ((E)-2,2-diethyl-3'-[2-[2-(4-isopropyl) thiazolyl]ethenyl]succinanilic acid, CAS 121230-22-6) is described. In isolated guinea pig ileum, MCI-826 inhibited LTD4 (a peptide leukotriene, 10(-9) mol/l)-induced contraction in a concentration-dependent manner with an IC50 of 6.8 x 10(-12) mol/l. It had no effect on histamine (10(-5) mol/l)-, serotonin (2.5 x 10(-5) mol/l)-, or acetylcholine (5.5 x 10(-6) mol/l)- induced contractions in isolated guinea pig ileum. In isolated guinea pig trachea, MCI-826 demonstrated competitive antagonism of the contractile activity of LTD4 and LTE4 with pA2 values of 9.0 and 8.8, respectively. MCI-826 inhibited LTC4-induced contraction in a concentration-dependent manner. However, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, MCI-826 (10(-6) mol/l) produced no effect on LTC4 concentration-response curves in guinea pig trachea. In the in vivo study, the oral administration of MCI-826 caused a dose-dependent inhibition of LTC4- and LTD4-induced bronchoconstrictions in guinea pigs with an ED50 of 0.049 and 0.013 mg/kg, respectively. However, MCI-826 (3 mg/kg p.o.) showed no effect on histamine-induced bronchoconstriction in guinea pigs. The pharmacological half-life of orally administered MCI-826 as assessed by LTD4-induced bronchoconstriction was more than 12 h in guinea pigs. MCI-826 also inhibited antigen-induced bronchoconstriction in a dose-dependent manner with a MID (minimum dose that causes significant inhibition) of 0.1 mg/kg p.o. in guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharmaceuticals Laboratory, Research Center, Mitsubishi Kasei Corporation, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: E
authors.initials: E
authors.lastname: Nakao
authors.forename: S
authors.initials: S
authors.lastname: Kadowaki
authors.forename: K
authors.initials: K
authors.lastname: Umezu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010400:Penicillin G / Q000276:immunology; D011738:Pyrilamine / Q000494:pharmacology; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
chemical_list: D001993:Bronchodilator Agents; D006633:Histamine Antagonists; D020024:Leukotriene Antagonists; D013844:Thiazoles; C077265:MCI 826; D017997:Leukotriene C4; D017998:Leukotriene D4; D011738:Pyrilamine; D000109:Acetylcholine; D010400:Penicillin G