Abstract:The dissociation constants (KB) at the LTD4 receptor on guinea pig trachea of a series of monocyclic and bicyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides have been measured. The KB was found to be remarkably tolerant of changes in the electronic constitution and lipophilicity of the bicyclic ring system (template). Thus, N-[4[[6-[[(cyclopentyloxy)carbonyl]amino]benzimidazol-1- yl]methyl]-3-methoxybenzoyl]benzenesulfonamide (11a) and N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]benzo[b]t… Show more
“…However, the transfer‐hydrogenation was not applicable to the benzyl derivatives 5‐Ig‐5‐IIIg , where debenzylation under conditions A or B would be the major reaction pathway. Instead of hydrogenation, reductions were carried out with stannous chloride (Table , conditions C) to overcome this undesirable reaction pathway . The corresponding benzylated derivatives 3‐Ig‐3‐IIIg were obtained in moderate yields of 71, 35, and 41 % yields, respectively.…”
N‐Alkylations of monosubstituted benzotriazoles yield isomeric products with distinct topology, i. e. 1H‐ or to 2H‐isomers. Therefore, the molecular shape of these compounds varies and this results in distinct biological and physical properties. Herein, a protocol for the simple synthesis of various alkyl‐aminobenzotriazoles using 5‐nitrobenzotriazole is reported. This synthetic approach furnishes 2‐alkyl‐5‐nitro‐2H‐benzotriazoles as major products in most of the attempted cases. All three obtained isomers were separable from each other by standard column chromatography. In addition, three alternative approaches furnishing selectively substituted alkyl‐amino‐1H‐benzotriazoles are described. Finally, a library of sixty‐eight N‐benzotriazoylureas and six N‐benzotriazoylthioureas was synthesized by reactions with either isocyanates (phenyl chloroformate) or isothiocyanates.
“…However, the transfer‐hydrogenation was not applicable to the benzyl derivatives 5‐Ig‐5‐IIIg , where debenzylation under conditions A or B would be the major reaction pathway. Instead of hydrogenation, reductions were carried out with stannous chloride (Table , conditions C) to overcome this undesirable reaction pathway . The corresponding benzylated derivatives 3‐Ig‐3‐IIIg were obtained in moderate yields of 71, 35, and 41 % yields, respectively.…”
N‐Alkylations of monosubstituted benzotriazoles yield isomeric products with distinct topology, i. e. 1H‐ or to 2H‐isomers. Therefore, the molecular shape of these compounds varies and this results in distinct biological and physical properties. Herein, a protocol for the simple synthesis of various alkyl‐aminobenzotriazoles using 5‐nitrobenzotriazole is reported. This synthetic approach furnishes 2‐alkyl‐5‐nitro‐2H‐benzotriazoles as major products in most of the attempted cases. All three obtained isomers were separable from each other by standard column chromatography. In addition, three alternative approaches furnishing selectively substituted alkyl‐amino‐1H‐benzotriazoles are described. Finally, a library of sixty‐eight N‐benzotriazoylureas and six N‐benzotriazoylthioureas was synthesized by reactions with either isocyanates (phenyl chloroformate) or isothiocyanates.
“…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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
