The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist.
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.
Krell
R D
RD
Biomedical Research Department, ICI Americas Inc., Wilmington, DE 19897.
Aharony
D
D
Buckner
C K
CK
Keith
R A
RA
Kusner
E J
EJ
Snyder
D W
DW
Bernstein
P R
PR
Matassa
V G
VG
Yee
Y K
YK
Brown
F J
FJ
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001986:Bronchial Spasm / Q000188:drug therapy; D002199:Capillary Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004417:Dyspnea / Q000188:drug therapy; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D048448:Phenylcarbamates; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
D007211:Indoles; D048448:Phenylcarbamates; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013449:Sulfonamides; D014105:Tosyl Compounds; C062735:zafirlukast