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Abdel Naser Zaid - One of the best experts on this subject based on the ideXlab platform.
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Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)Xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
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novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl Xanthines as potent and selective a2b adenosine receptor antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified s...
Christa E Muller - One of the best experts on this subject based on the ideXlab platform.
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fast efficient and versatile synthesis of 6 amino 5 carboxamidouracils as precursors for 8 substituted Xanthines
Frontiers in Chemistry, 2019Co-Authors: Daniel Marx, Christa E Muller, Lukas M Wingen, Gregor Schnakenburg, Matthias ScholzAbstract:Substituted xanthine derivatives are important bioactive molecules. Herein we report on a new, practical synthesis of 6-amino-5-carboxamidouracils, the main building blocks for the preparation of 8-substituted Xanthines, by condensation of 5,6-diaminouracil derivatives and various carboxylic acids using the recently developed non-hazardous coupling reagent COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate). Optimized reaction conditions led to the precipitation of pure products after only 5 to 10 min of reaction time. The method tolerates a variety of substituted 5,6-diaminouracil and carboxylic acid derivatives as starting compounds resulting in most cases in more than 80% isolated yield. Regioselectivity of the reaction yielding only the 5-carboxamido-, but not the 6-carboxamidouracil derivatives, was unambiguously confirmed by single X-ray crystallography and multidimensional NMR experiments. The described method represents a convenient, fast access to direct precursors of 8-substituted Xanthines under mild conditions without the necessity of hazardous coupling or chlorinating reagents.
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Data_Sheet_2_Fast, Efficient, and Versatile Synthesis of 6-amino-5-carboxamidouracils as Precursors for 8-Substituted Xanthines.PDF
2019Co-Authors: Daniel Marx, Christa E Muller, Lukas M Wingen, Gregor Schnakenburg, Matthias S. ScholzAbstract:Substituted xanthine derivatives are important bioactive molecules. Herein we report on a new, practical synthesis of 6-amino-5-carboxamidouracils, the main building blocks for the preparation of 8-substituted Xanthines, by condensation of 5,6-diaminouracil derivatives and various carboxylic acids using the recently developed non-hazardous coupling reagent COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate). Optimized reaction conditions led to the precipitation of pure products after only 5 to 10 min of reaction time. The method tolerates a variety of substituted 5,6-diaminouracil and carboxylic acid derivatives as starting compounds resulting in most cases in more than 80% isolated yield. Regioselectivity of the reaction yielding only the 5-carboxamido-, but not the 6-carboxamidouracil derivatives, was unambiguously confirmed by single X-ray crystallography and multidimensional NMR experiments. The described method represents a convenient, fast access to direct precursors of 8-substituted Xanthines under mild conditions without the necessity of hazardous coupling or chlorinating reagents.
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synthesis and preliminary evaluation of new 1 and 3 1 2 hydroxy 3 phenoxypropyl Xanthines from 2 amino 2 oxazolines as potential a1 and a2a adenosine receptor antagonists
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Stephane Massip, Christa E Muller, Jean Guillon, Daniela C G Bertarelli, Jeanjacques Bosc, Jeanmichel Leger, Svenja Lacher, Cecile Bontemps, Thibaut Dupont, Christian JarryAbstract:The development of potent and selective adenosine receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of adenosine receptor antagonists and have been widely developed in terms of affinity and selectivity for adenosine receptors. We recently developed new original pathways for the synthesis of xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and β-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic xanthine derivatives 1 – 4 from 5 , and their evaluation as adenosine A 1 , A 2A and A 3 receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the xanthine core, while its introduction in the 1-position of the xanthine moiety led to a large decrease in adenosine receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)xanthine ( 2n ) was the most potent and selective A 2A antagonist of the present series ( K i = 44 nM, ≫200-fold selective vs A 1 ). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylxanthine ( 3f ) was identified as a potent ( K i A 1 = 21 nM) and highly selective (≫350-fold vs A 2A and A 3 receptor) adenosine A 1 receptor antagonist.
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synthesis of paraxanthine analogs 1 7 disubstituted Xanthines and other Xanthines unsubstituted at the 3 position structure activity relationships at adenosine receptors
Journal of Medicinal Chemistry, 1993Co-Authors: Christa E Muller, Dan Shi, M Manning, John W DalyAbstract:Synthetic procedures for the preparation of various 3-unsubstituted Xanthines, including paraxanthine analogs (1,7-disubstituted Xanthines) and 1,8-disubstituted Xanthines, were developed. Silylation of 1-substituted Xanthines followed by alkylation at the 7-position provides a facile route to paraxanthine analogs. Regioselective alkylation of tris(trimethylsilyl)-6-aminouracil provides 3-substituted 6-aminouracils, which are converted to 1,8-disubstituted Xanthines by standard procedures. The ring closure of 3-substituted 5-cyclopentanecarboxamido- and 5-(benzoylamino)-6-aminouracils requires drastic reaction conditions. Affinity for brain A1 and A2 adenosine receptors was determined in binding assays for these and other Xanthines with substituents in 1-, 3-, 7-, 8-, and 9-positions. Substitution at the 1-position was necessary for high affinity at adenosine receptors. 1,3-Disubstituted Xanthines generally had higher affinity than 1,7-disubstituted Xanthines. 1,8-Disubstituted Xanthines had high affinity for adenosine receptors; some were highly selective for A1 receptors.
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general synthesis and properties of 1 monosubstituted Xanthines
Synthesis, 1993Co-Authors: Christa E MullerAbstract:A general convenient synthesis of 1-monosubstituted Xanthines (7H-imidazo[4,5-d]pyrimidine-2,6(1H,3H)-diones), starting from 3-substituted 6-aminouracils, is described. After conversion of the 6-aminouracils to the corresponding 5,6-diaminouracils, reaction with formic acid, or with triethyl orthoformate, leads to the novel Xanthines in good to excellent yields, while ring closure in alkaline medium, which is commonly used in xanthine synthesis, is not successful
Pier Giovanni Baraldi - One of the best experts on this subject based on the ideXlab platform.
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Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)Xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
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novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl Xanthines as potent and selective a2b adenosine receptor antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified s...
Maurizio Recanatini - One of the best experts on this subject based on the ideXlab platform.
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Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)Xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
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novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl Xanthines as potent and selective a2b adenosine receptor antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified s...
Delia Preti - One of the best experts on this subject based on the ideXlab platform.
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Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)Xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
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novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl Xanthines as potent and selective a2b adenosine receptor antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified s...