“…Replacement of the quinoline by phenyl (19, 20, and 21) or naphthyl (22 and 23) reduced the activity at least 100-fold, indicating that the quinoline nitrogen plays a crucial role in binding to the receptor. Substitution of the quinoline for several other nitrogen-containing heterocyclic systems (24)(25)(26)(27)(28)(29)(30)(31) does not yield compounds with improved activities (compare 24, 25, 29, and 30 with reference compound 14), with the 1-(1-(ethoxyethyl)-2-benzimidazolyl) derivative 25 having the lowest activity. The loss of activity may be either due to steric bulk or electronic factors.…”
Section: Resultsmentioning
confidence: 99%
“…probilukast (SK&F 104353). [23][24][25][26][27][28] Later new leads were discovered, which led to the development of a wide range of compounds such as the indole zafirlukast (ICI 204,219), [29][30][31][32][33] the benzamide pranlukast (ONO-1078), 34,35 38 and montelukast (MK-476), 39 as highly potent antagonists at the CysLT 1 receptor (see Scheme 1 for the structures of these CysLT 1 antagonists).…”
Section: Introductionmentioning
confidence: 99%
“…At first the development of new CysLT 1 antagonist was mainly inspired by FPL 55712 or LTD 4 analogues, e.g. probilukast (SK&F 104353). − Later new leads were discovered, which led to the development of a wide range of compounds such as the indole zafirlukast (ICI 204,219), − the benzamide pranlukast (ONO-1078), , the thiazole Ro 24-5913 [(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4-oxobutanoic acid] , and quinolines such as RG 12553 [5-[7-[[3-(2-quinolinylmethoxy)phenyl]methoxy]-4-oxo-4 H -1-benzopyran-2-yl]-1 H -tetrazole] and montelukast (MK-476), as highly potent antagonists at the CysLT 1 receptor (see Scheme for the structures of these CysLT 1 antagonists). 1 Potent CysLT 1 Receptor Antagonists …”
The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.
“…Replacement of the quinoline by phenyl (19, 20, and 21) or naphthyl (22 and 23) reduced the activity at least 100-fold, indicating that the quinoline nitrogen plays a crucial role in binding to the receptor. Substitution of the quinoline for several other nitrogen-containing heterocyclic systems (24)(25)(26)(27)(28)(29)(30)(31) does not yield compounds with improved activities (compare 24, 25, 29, and 30 with reference compound 14), with the 1-(1-(ethoxyethyl)-2-benzimidazolyl) derivative 25 having the lowest activity. The loss of activity may be either due to steric bulk or electronic factors.…”
Section: Resultsmentioning
confidence: 99%
“…probilukast (SK&F 104353). [23][24][25][26][27][28] Later new leads were discovered, which led to the development of a wide range of compounds such as the indole zafirlukast (ICI 204,219), [29][30][31][32][33] the benzamide pranlukast (ONO-1078), 34,35 38 and montelukast (MK-476), 39 as highly potent antagonists at the CysLT 1 receptor (see Scheme 1 for the structures of these CysLT 1 antagonists).…”
Section: Introductionmentioning
confidence: 99%
“…At first the development of new CysLT 1 antagonist was mainly inspired by FPL 55712 or LTD 4 analogues, e.g. probilukast (SK&F 104353). − Later new leads were discovered, which led to the development of a wide range of compounds such as the indole zafirlukast (ICI 204,219), − the benzamide pranlukast (ONO-1078), , the thiazole Ro 24-5913 [(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4-oxobutanoic acid] , and quinolines such as RG 12553 [5-[7-[[3-(2-quinolinylmethoxy)phenyl]methoxy]-4-oxo-4 H -1-benzopyran-2-yl]-1 H -tetrazole] and montelukast (MK-476), as highly potent antagonists at the CysLT 1 receptor (see Scheme for the structures of these CysLT 1 antagonists). 1 Potent CysLT 1 Receptor Antagonists …”
The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.
“…Originally the development of new Cys LT 1 antagonists was mainly inspired by either FPL 55712 (sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]-4-oxo-8-propyl-4 H -1-benzopyran-2-carboxylate), the first Cys LT 1 receptor antagonist, or LTD 4 analogues with antagonistic properties. − Later new lead structures were discovered, leading to the development of a wide range of compounds such as indoles (e.g., ICI 204,219/Zafirlukast − ), benzamides (e.g., ONO-1078/Pranlukast , ), thiazoles (e.g., Ro 24-5913/[( E )-4-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4-oxobutanoic acid] , ), and quinolines (e.g., RG 12553/[5-[7-[[3-(2-quinolinylmethoxy)phenyl]methoxy]-4-oxo-4 H -1-benzopyran-2-yl]-1 H -tetrazole] and MK-476/Montelukast) as highly potent antagonists at the CysLT 1 receptor (Chart ). 1 …”
The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT1 affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT1 affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT1 receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT1 receptor antagonists known to date, and they are useful in the development of a CysLT1 antagonist model, which is discussed in the companion paper.
“…BAY x7195 is a novel cysteinyl‐leukotriene receptor antagonist (Abram et al , 1993) with marked potency against these agonists in guinea‐pig isolated tracheal tissue. The negative log molar dissociation constant (p K B ) against LTD 4 and LTE 4 have been found to be 8.4 and 9.1, respectively (Abram et al , 1993; latter unpublished). In addition, when the metabolism of LTC 4 to LTD 4 was inhibited, BAY x7195 also weakly inhibited the LTC 4 ‐induced contractions with a p K B of 6.1 (Abram et al , unpublished data).…”
1 The novel leukotriene antagonist Bay x7195, has been evaluated against bronchoconstriction induced by leukotriene D 4 (LTD 4 ), the thromboxane A 2 (TXA 2 ) mimetic U46619, histamine and antigen, in the guinea-pig in vivo by use of a modi®ed Konzett-RoÈ ssler preparation. 2 LTD 4 , given intravenously (i.v.) at 1 or 3 mg kg 71 in the presence of indomethacin and sotalol, caused a 50 ± 70% maximal bronchoconstriction in most animals. 5 When given intravenously, in the presence of selected antagonists, BAY x7195 caused a dose-related reduction in the antigen-induced response, with an approximate ID 50 of 2 mg kg 71 . 6 At 3 mg kg 71 , i.v., a dose which abolished the response to LTD 4 , BAY x7195 had no eect on U46619-or histamine-induced bronchoconstriction. 7 BAY x7195 is a potent, selective and long acting antagonist of LTD 4 -induced bronchoconstriction, in an anaesthetized, ventilated guinea-pig model. It is therefore worthy of clinical evaluation in diseases believed to involve the sulphidopeptide leukotrienes, such as asthma.
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