BIOMAT Database Logo BIOMAT Database Logo

The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist. 1990

R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
Biomedical Research Department, ICI Americas Inc., Wilmington, DE 19897.

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.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D008297 Male Males
D011971 Receptors, Immunologic Cell surface molecules on cells of the immune system that specifically bind surface molecules or messenger molecules and trigger changes in the behavior of cells. Although these receptors were first identified in the immune system, many have important functions elsewhere. Immunologic Receptors,Immunologic Receptor,Immunological Receptors,Receptor, Immunologic,Receptors, Immunological
D001986 Bronchial Spasm Spasmodic contraction of the smooth muscle of the bronchi. Bronchospasm,Bronchial Spasms,Bronchospasms,Spasm, Bronchial,Spasms, Bronchial
D002199 Capillary Permeability The property of blood capillary ENDOTHELIUM that allows for the selective exchange of substances between the blood and surrounding tissues and through membranous barriers such as the BLOOD-AIR BARRIER; BLOOD-AQUEOUS BARRIER; BLOOD-BRAIN BARRIER; BLOOD-NERVE BARRIER; BLOOD-RETINAL BARRIER; and BLOOD-TESTIS BARRIER. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (TIGHT JUNCTIONS) which may limit large molecule movement. Microvascular Permeability,Permeability, Capillary,Permeability, Microvascular,Vascular Permeability,Capillary Permeabilities,Microvascular Permeabilities,Permeabilities, Capillary,Permeabilities, Microvascular,Permeabilities, Vascular,Permeability, Vascular,Vascular Permeabilities
D002621 Chemistry A basic science concerned with the composition, structure, and properties of matter; and the reactions that occur between substances and the associated energy exchange.
D004417 Dyspnea Difficult or labored breathing. Orthopnea,Platypnea,Recumbent Dyspnea,Rest Dyspnea,Trepopnea,Breathlessness,Shortness of Breath,Breath Shortness,Dyspnea, Recumbent,Dyspnea, Rest,Dyspneas, Rest
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000403 Airway Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Airway Resistances,Resistance, Airway,Resistances, Airway

Related Publications

R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
Preclinical exploration of the potential antiinflammatory properties of the peptide leukotriene antagonist ICI 204,219 (Accolate).
November 1994, Annals of the New York Academy of Sciences,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
Inhibition of allergic bronchoconstriction in asthmatics by the leukotriene-antagonist ICI-204,219.
January 1991, Advances in prostaglandin, thromboxane, and leukotriene research,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis.
June 1995, American journal of respiratory and critical care medicine,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
Inhibition of platelet-activating factor-induced bronchoconstriction by the leukotriene D4 receptor antagonist ICI 204,219.
January 1993, The American review of respiratory disease,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
The protective effect of inhaled leukotriene D4 receptor antagonist ICI 204,219 against exercise-induced asthma.
June 1993, The American review of respiratory disease,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist.
November 1987, The Journal of pharmacology and experimental therapeutics,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
In vivo pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist.
November 1987, The Journal of pharmacology and experimental therapeutics,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma.
May 1992, The Journal of allergy and clinical immunology,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
The effect of the oral leukotriene antagonist, ICI 204,219, on leukotriene D4 and histamine-induced cutaneous vascular reactions in man.
January 1991, The Journal of allergy and clinical immunology,
R D Krell, and D Aharony, and C K Buckner, and R A Keith, and E J Kusner, and D W Snyder, and P R Bernstein, and V G Matassa, and Y K Yee, and F J Brown
Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by the oral LTD4 receptor antagonist ICI 204,219.
April 1990, The American review of respiratory disease,
Copied contents to your clipboard!