title: Evolution of a series of peptidoleukotriene antagonists: synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles.
abstract: 1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.
authors.affiliation: Department of Medicinal Chemistry, ICI Pharmaceuticals Group, Wilmington, Delaware 19897.
authors.forename: V G
authors.initials: VG
authors.lastname: Matassa
authors.forename: T P
authors.initials: TP
authors.lastname: Maduskuie
authors.forename: H S
authors.initials: HS
authors.lastname: Shapiro
authors.forename: B
authors.initials: B
authors.lastname: Hesp
authors.forename: D W
authors.initials: DW
authors.lastname: Snyder
authors.forename: D
authors.initials: D
authors.lastname: Aharony
authors.forename: R D
authors.initials: RD
authors.lastname: Krell
authors.forename: R A
authors.initials: RA
authors.lastname: Keith
mesh_terms: D000818:Animals; D004417:Dyspnea / Q000139:chemically induced / Q000517:prevention & control; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D007211:Indoles; D011720:Pyrazoles; D013189:SRS-A