Substituted 3-(phenylmethyl)-1H-indole-5-carboxamides and 1-(phenylmethyl)indole-6-carboxamides as potent, selective, orally active antagonists of the peptidoleukotrienes

Abstract

Substituted indole-5-carboxamides and indole-6-carboxamides have been found to be potent and selective antagonists of the peptidoleukotrienes. Initial derivatives of these series (4-[[5-[(cyclopentylmethyl)carbamoyl]-1-methylindol-3-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (5a) and 4-[[6-[(cyclopentylmethyl)carbamoyl]-3-methylindol-1-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (6a), respectively), when compared to the corresponding indole amides (e.g. 28 and 29), were found to be approximately 10-fold less potent in vitro and substantially less active when administered orally to guinea pigs. Efforts to improve the potency of the title series by variation of the amide, indole, or sulfonamide substituents led to compounds of comparable in vitro potency to ICI 204,219, but of somewhat lower oral activity. A trend which suggested that more lipophilic transposed amides were needed to increase oral activity was exploited with some success and has led to the discovery of 5q (4-[[5-[(2-ethylbutyl)-carbamoyl]-1-ethylindol-3-yl]methyl]- 3- methoxy-N-[(2-methylphenyl)sulfonyl]benzamide), a transposed amide with subnanomolar affinity for the leukotriene receptor and an oral ED50 of 5 mg/kg in a model of asthma in guinea pigs. In this model, ICI 204,219 was active at 0.4 mg/kg. The absolute bioavailability of 5q has been found to be 28% in the rat, as compared to 68% for ICI 204,219, with significant levels of 5q observed in the blood of rats up to 24 h postdose.

Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB1 receptor antagonist

“…In addition, various carboxamide and sulfonamide derivatives exhibited a pattern of no effect or partial agonist effects in vivo despite good binding affinity (Singer et al, 1998). These latter derivatives also showed potent antagonist activity for the peptidoleukotrienes, a class of eicosanoids (Jacobs et al, 1993; Matassa et al, 1990). …”

Antimicrobial and in Silico Admet Screening of Novel (E)-N-(2-(1h-Indol-3-Yl-Amino) Vinyl)-3-(1-Methyl-1h-Indol-3-Yl)-3-Phenylpropanamide Derivatives

“…Based on the above reports, we explored the synthesis of new indole propanamide derivatives 5(a-e) to be potent antibacterial and antifungal agents when tested against precarious pathogenic microorganisms such as Pseudomonas aureginosa, Escherichia coli, Vibrio cholerae, Staphylococcus aureus and antifungal activity against Candida albicans, Aspergillus niger, Penicillin chrysogenum and Cladosporium oxysporum. The rationality in investigating the biopotency of indole-3-propanamide derivatives is due to its use as precursors to obtain several biologically active molecules, especially for the treatment of brain disorder [6], as tyrosine kinase inhibitors, inhibitors of epidermal growth factor (EGF) receptor [7], immunosuppressive activity [8] anti-allergic [9] and inflammation inhibitors [10]. Thus, indole-3-propanamides have become an important precursor for various pharmaceutically important compounds [11][12][13], and there is flexibility in exploring indole-3propanamide derivatives randomly for various biological activities to get suitable hits.…”

New N-(Pyridin-4-yl)-(indol-3-yl)acetamides and Propanamides as Antiallergic Agents

“…20 Although the corresponding indolylalkylamides exhibited only moderate anti-edematous effect, to our surprise, results of pharmacological screening tests revealed that some of these compounds significantly inhibited IL-4, IL-5 biosynthesis and/or histamine release. These data and the fact that indole constitutes the central core of numerous potent LTD 4 antagonists, [21][22][23] PAF antagonists, 24 or inhibitors of FLAP, 12 prompted us to carry out an extensive pharmacomodulation in this series. We report here the results of in vitro and in vivo investigations in the N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 (Table 3).…”