EVOLUTION OF A SERIES OF PEPTIDOLEUKOTRIENE ANTAGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,3,5-SUBSTITUTED INDOLES AND INDAZOLES

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—10-11M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) ≤10-9M 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]-l-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≤ 10-9M on guinea pig trachea. © 1990, American Chemical Society. All rights reserved.