title: In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist.
abstract: ICI 198,615 is a representative compound from a new class of peptide leukotriene (LT) receptor antagonists. In isolated guinea pig trachea and parenchymal lung strips, ICI 198,615 demonstrated competitive antagonism of the contractile activity of LTD4 and LTE4 with pA2 values of 10.1 to 9.5, respectively. The compound also appeared to antagonize the contractile activity of LTC4 in guinea pig trachea; however, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, ICI 198, 615 provided a pKB value of 5.3, indicating weak antagonism at the LTC4 receptor. ICI 198,615 was also a potent antagonist of LTC4 and LTD4 in isolated human bronchi and pulmonary veins with pKa values of 9.75 +/- 0.32 to 9.20 +/- 0.24, respectively. When evaluated for activity on a broad variety of non-LT receptors, the compound displayed a minimal selectivity of 6310 and a maximal selectivity of greater than 125,000 for the LTE4 receptor. These in vitro studies indicate that ICI 198,615 is the most potent and selective peptide LT receptor antagonist described to date.
authors.affiliation: Department of Pharmacology, Stuart Pharmaceuticals, Division of ICI Americas Inc., Wilmington, Delaware.
authors.forename: D W
authors.initials: DW
authors.lastname: Snyder
authors.forename: R E
authors.initials: RE
authors.lastname: Giles
authors.forename: R A
authors.initials: RA
authors.lastname: Keith
authors.forename: Y K
authors.initials: YK
authors.lastname: Yee
authors.forename: R D
authors.initials: RD
authors.lastname: Krell
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
chemical_list: D000098:Acetophenones; D007191:Indazoles; D011720:Pyrazoles; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D013777:Tetrazoles; C054217:ICI 198615; C044660:LY 171883