Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles

Article abstract of DOI:10.1021/jm00168a037

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 arysulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants K(B) in the range 10^-9-10^-11 M on guinea pig trachea against LTE₄ as agonist and inhibition constants (K(i)) ≤ 10^-9 M on guinea pig parenchymal membranes against [³H]LTD₄. A number of compounds were orally effective at doses ≤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-methyl]benzenesulfonamide, ICI 204,219; pK(B) = 9.67 ± 0.13, K(i) = 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 K(B) ≤ 10^-9 M on guinea pig trachea.