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 t… Show more
“…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). …”
Rimonabant, the prototypic antagonist of cannabinoid CB 1 receptors, has been reported to have inverse agonist properties at higher concentrations, which may complicate its use as a tool for mechanistic evaluation of cannabinoid pharmacology. Consequently, recent synthesis efforts have concentrated on discovery of a neutral antagonist using a variety of structural templates. The purpose of this study was to evaluate the pharmacological properties of the putative neutral cannabinoid CB 1 receptor antagonist O-2050, a sulfonamide side chain analog of Δ 8 -tetrahydrocannabinol. O-2050 and related sulfonamide cannabinoids exhibited good affinity for both cannabinoid CB 1 and CB 2 receptors. While the other sulfonamide analogs produced cannabinoid agonist effects in vivo (e.g., activity suppression, antinociception, and hypothermia), O-2050 stimulated activity and was inactive in the other two tests. O-2050 also decreased food intake in mice, an effect that was reminiscent of that produced by rimonabant. Unlike rimonabant, however, O-2050 did not block the effects of cannabinoid agonists in vivo, even when administered i.c.v. In contrast, O-2050 antagonized the in vitro effects of cannabinoid agonists in [ 35 S]GTPγS and mouse vas deferens assays without having activity on its own in either assay. Further evaluation revealed that O-2050 fully and dose-dependently substituted for Δ 9 -tetrahydrocannabinol in a mouse drug discrimination procedure (a cannabinoid agonist effect) and that it inhibited forskolin-stimulated cyclic AMP signaling with a maximum efficacy of approximately half that of the full agonist CP55,940 [(−)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol]. Together, these results suggest that O-2050 is not a viable candidate for classification as a neutral cannabinoid CB 1 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). …”
Rimonabant, the prototypic antagonist of cannabinoid CB 1 receptors, has been reported to have inverse agonist properties at higher concentrations, which may complicate its use as a tool for mechanistic evaluation of cannabinoid pharmacology. Consequently, recent synthesis efforts have concentrated on discovery of a neutral antagonist using a variety of structural templates. The purpose of this study was to evaluate the pharmacological properties of the putative neutral cannabinoid CB 1 receptor antagonist O-2050, a sulfonamide side chain analog of Δ 8 -tetrahydrocannabinol. O-2050 and related sulfonamide cannabinoids exhibited good affinity for both cannabinoid CB 1 and CB 2 receptors. While the other sulfonamide analogs produced cannabinoid agonist effects in vivo (e.g., activity suppression, antinociception, and hypothermia), O-2050 stimulated activity and was inactive in the other two tests. O-2050 also decreased food intake in mice, an effect that was reminiscent of that produced by rimonabant. Unlike rimonabant, however, O-2050 did not block the effects of cannabinoid agonists in vivo, even when administered i.c.v. In contrast, O-2050 antagonized the in vitro effects of cannabinoid agonists in [ 35 S]GTPγS and mouse vas deferens assays without having activity on its own in either assay. Further evaluation revealed that O-2050 fully and dose-dependently substituted for Δ 9 -tetrahydrocannabinol in a mouse drug discrimination procedure (a cannabinoid agonist effect) and that it inhibited forskolin-stimulated cyclic AMP signaling with a maximum efficacy of approximately half that of the full agonist CP55,940 [(−)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol]. Together, these results suggest that O-2050 is not a viable candidate for classification as a neutral cannabinoid CB 1 receptor antagonist.
“…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.…”
<p><strong>Objective: </strong>Synthesis, <em>in silico</em> absorption, distribution, metabolism, excretion, toxicity (ADMET) and <em>in vitro</em> antimicrobial screening of (<em>E</em>)-<em>N</em>-(2-(1<em>H</em>-indol-3-ylamino) vinyl)-3-(1-methyl-1<em>H</em>-indol-3-yl)-3-phenylpropanamide derivatives.<strong></strong></p><p><strong>Methods: </strong>(<em>E</em>)-<em>N</em>-(2-(1<em>H</em>-indol-3-ylamino) vinyl)-3-(1-methyl-1<em>H</em>-indol-3-yl)-3 phenylpropane-amide derivatives were synthesized by combining indole ethanolamine and substituted Meldrum’s adduct. The synthesized compounds were subjected to <em>in vitro</em> antimicrobial study by cup plate method and <em>in silico</em> ADMET properties using ACD/I-Lab 2.0.</p><p><strong>Results: </strong>The <em>in vitro </em>antimicrobial screening against precarious pathogenic microorganisms <em>viz</em>, <em>Pseudomonas aureginosa</em>, <em>Staphylococcus aureus,</em> <em>Escherichia coli, </em><em>Vibrio cholerae</em>, and the antifungal activity against <em>Candida albicans, </em><em>Aspergillus niger</em>, <em>Penicillin chrysogenum</em> and <em>Cladosporium oxysporum</em> strains. The results revealed that compounds 5b, 5c, 5d and 5e showed good antimicrobial property and obeyed the <em>in silico</em> pharmacokinetic parameters.</p><p><strong>Conclusion: </strong>The encouraging results exhibited by the compounds (<em>E</em>)-<em>N</em>-(2-(1<em>H</em>-indol-3-ylamino) vinyl)-3-(1-methyl-1<em>H</em>-indol-3-yl)-3-phenyl propanamide derivatives, 5(a-e) can be explored as possible hits in antimicrobial therapy. The molecules obey the Lipinski rule of five when tested <em>in silico </em>and can be used in understanding the quantitative structure-activity relationship (QSAR) parameters.</p>
“…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).…”
A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.
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