Krell R D, Aharony D, Buckner C K, Keith R A, Kusner E J, Snyder D W, Bernstein P R, Matassa V G, Yee Y K, Brown F J
Biomedical Research Department, ICI Americas Inc., Wilmington, DE 19897.
Am Rev Respir Dis. 1990 Apr;141(4 Pt 1):978-87. doi: 10.1164/ajrccm/141.4_Pt_1.978.
ICI 204,219 (4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethy l)-3- methoxy-N-o-tolylsulfonylbenzamide) was designed as a peptide leukotriene (LT) antagonist. The compound is a competitive antagonist of LTD4- and LTE4-induced contraction of guinea pig lung tracheal and parenchymal strips with an apparent negative log molar dissociation constant (KB) of approximately 9.6. ICI 204,219 did not antagonize LTC4-induced contractions of guinea pig trachea when the metabolism of LTC4 to LTD4 and, subsequently, to LTE4 was inhibited. The compound inhibited the binding of [3H]LTD4, [3H]LTE4, and [3H]ICI 198,615 (a potent LT antagonist from a different heterocyclic series) to guinea pig lung parenchymal membranes in a competitive manner, and also inhibited [3H]ICI 198,615 binding to human lung parenchymal membranes. ICI 204,219 did not bind to a variety of other receptors when evaluated at concentrations 1,000- to 10,000-fold higher than the apparent KB value for peptide LT receptors. When administered orally, intravenously, or by aerosol, the compound provided dose-related antagonism of the airway effects of aerosol LTD4 in conscious guinea pigs. ED50 values and pharmacodynamic t1/2 (min) for oral, intravenous and aerosol routes of administration were, respectively: 0.52 mumol/kg, greater than 816 min; 0.046 mumol/kg, 85 min; 5.1 x 10(-6) M, 109 min. ICI 204,219 also produced dose-related inhibition of the effects of LTC4 (aerosol or intravenous administration) on pulmonary mechanics in anesthetized guinea pigs when administered orally, intraduodenally, intravenously, or by aerosol. The compound also reversed bronchospasm produced by LTs. Aerosol ovalbumin antigen-induced bronchospasm in guinea pigs was both inhibited and reversed by ICI 204,219. Lastly, the compound inhibited LTD4-induced increases in cutaneous vascular permeability in guinea pigs, being 1,006- and 679-fold more potent than the first generation LT antagonists LY 171,883 and FPL 55712, respectively. ICI 204,219 is a potent, selective, orally active LT antagonist currently undergoing clinical trials.
ICI 204,219（4-(5-环戊氧基羰基氨基-1-甲基吲哚-3-基甲基)-3-甲氧基-N-邻甲苯磺酰基苯甲酰胺）被设计为一种肽白三烯（LT）拮抗剂。该化合物是LTD4和LTE4诱导的豚鼠肺气管和实质条收缩的竞争性拮抗剂，其表观负对数摩尔解离常数（KB）约为9.6。当LTC4向LTD4以及随后向LTE4的代谢被抑制时，ICI 204,219不会拮抗LTC4诱导的豚鼠气管收缩。该化合物以竞争性方式抑制[3H]LTD4、[3H]LTE4和[3H]ICI 198,615（来自不同杂环系列的一种强效LT拮抗剂）与豚鼠肺实质膜的结合，并且也抑制[3H]ICI 198,615与人肺实质膜的结合。当在比肽LT受体的表观KB值高1000至10000倍的浓度下评估时，ICI 204,219不会与多种其他受体结合。当经口服、静脉内或气雾剂给药时，该化合物对清醒豚鼠气雾剂LTD4的气道效应具有剂量相关的拮抗作用。口服、静脉内和气雾剂给药途径的ED50值和药效学半衰期（分钟）分别为：0.52 μmol/kg，大于816分钟；0.046 μmol/kg，85分钟；5.1×10⁻⁶ M，109分钟。ICI 204,219经口服、十二指肠内、静脉内或气雾剂给药时，对麻醉豚鼠中LTC4（气雾剂或静脉内给药）对肺力学的影响也产生剂量相关的抑制作用。该化合物还能逆转由LTs引起的支气管痉挛。ICI 204,219可抑制并逆转豚鼠中由气雾剂卵清蛋白抗原诱导的支气管痉挛。最后，该化合物抑制豚鼠中LTD4诱导的皮肤血管通透性增加，其效力分别比第一代LT拮抗剂LY 171,883和FPL 55712强1006倍和679倍。ICI 204,219是一种强效、选择性、口服活性的LT拮抗剂目前正在进行临床试验
