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

J Med Chem. 1990 Jun;33(6):1781-90. doi: 10.1021/jm00168a037.

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.

MeSH terms

  • Animals
  • Dyspnea / chemically induced
  • Dyspnea / prevention & control
  • Guinea Pigs
  • In Vitro Techniques
  • Indazoles / chemical synthesis
  • Indazoles / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Muscle Contraction / drug effects
  • Pyrazoles / pharmacology*
  • SRS-A / antagonists & inhibitors*
  • SRS-A / toxicity
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Indoles
  • Pyrazoles
  • SRS-A