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Wouter De Looff - One of the best experts on this subject based on the ideXlab platform.
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bioisosteric replacements of the pyrazole moiety of rimonabant synthesis biological properties and molecular modeling investigations of thiazoles triazoles and Imidazoles as potent and selective cb1 cannabinoid receptor antagonists
Journal of Medicinal Chemistry, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C Mccreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter De LooffAbstract:Series of thiazoles, triazoles, and Imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB1 receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The thiazoles, triazoles, and Imidazoles elicited in vitroCB1 antagonistic activities and in general exhibited considerable CB1 vs CB2 receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure−activity relationship (SAR) study revealed a close correlation between the biological results in the imidazo...
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bioisosteric replacements of the pyrazole moiety of rimonabant synthesis biological properties and molecular modeling investigations of thiazoles triazoles and Imidazoles as potent and selective cb1 cannabinoid receptor antagonists
Journal of Medicinal Chemistry, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C Mccreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter De LooffAbstract:Series of thiazoles, triazoles, and Imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and Imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.
Josephus H M Lange - One of the best experts on this subject based on the ideXlab platform.
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bioisosteric replacements of the pyrazole moiety of rimonabant synthesis biological properties and molecular modeling investigations of thiazoles triazoles and Imidazoles as potent and selective cb1 cannabinoid receptor antagonists
Journal of Medicinal Chemistry, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C Mccreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter De LooffAbstract:Series of thiazoles, triazoles, and Imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB1 receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The thiazoles, triazoles, and Imidazoles elicited in vitroCB1 antagonistic activities and in general exhibited considerable CB1 vs CB2 receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure−activity relationship (SAR) study revealed a close correlation between the biological results in the imidazo...
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bioisosteric replacements of the pyrazole moiety of rimonabant synthesis biological properties and molecular modeling investigations of thiazoles triazoles and Imidazoles as potent and selective cb1 cannabinoid receptor antagonists
Journal of Medicinal Chemistry, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C Mccreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter De LooffAbstract:Series of thiazoles, triazoles, and Imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and Imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.
John F Hartwig - One of the best experts on this subject based on the ideXlab platform.
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regio and enantioselective n allylations of imidazole benzimidazole and purine heterocycles catalyzed by single component metallacyclic iridium complexes
ChemInform, 2009Co-Authors: Levi M Stanley, John F HartwigAbstract:Highly regio- and enantioselective iridium-catalyzed N-allylations of benzImidazoles, Imidazoles, and purines have been developed. N-Allylated benzImidazoles and Imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of nucleophile pK(a) on the rate of iridium-catalyzed N-allylation reactions. Kinetic studies on the allylation of benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the effects of the structures of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The data obtained from these studies have led to the development of N-allylations of benzImidazoles and Imidazoles in the absence of an exogenous base.
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regio and enantioselective n allylations of imidazole benzimidazole and purine heterocycles catalyzed by single component metallacyclic iridium complexes
Journal of the American Chemical Society, 2009Co-Authors: Levi M Stanley, John F HartwigAbstract:Highly regio- and enantioselective iridium-catalyzed N-allylations of benzImidazoles, Imidazoles, and purines have been developed. N-Allylated benzImidazoles and Imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustra...
S Viel - One of the best experts on this subject based on the ideXlab platform.
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regiocontrolled synthesis of 1 2 diaryl 1h Imidazoles by palladium and copper mediated direct coupling of 1 aryl 1h Imidazoles with aryl halides under ligandless conditions
ChemInform, 2006Co-Authors: Fabio Bellina, Silvia Cauteruccio, Luisa Mannina, Renzo Rossi, S VielAbstract:A large variety of 1,2-diaryl-1H-Imidazoles, including a selective COX-2 inhibitor, have been regioselectively synthesised in moderate to high yields by direct coupling of 1-aryl-1H-Imidazoles with aryl iodides or bromides in DMF in the presence of CsF and catalytic amounts of Pd(OAc)2 under ligandless conditions. A possible mechanism for this new highly regioselective C-2 arylation reaction, involving the formation of an organocopper(I) derivatives followed by a transmetallation reaction with an arylpalladium(II) halide species and a reductive elimination, is proposed. New one-step procedures for the synthesis of 1,2,5-triaryl-1H-Imidazoles, based on palladium- and copper-mediated arylation of 1-aryl-1H-Imidazoles, have also been developed. Interestingly, some imidazole derivatives prepared in this study have been found to exhibit significant cytotoxic activity against some human tumour cell lines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
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regioselective synthesis of 1 5 diaryl 1h Imidazoles by palladium catalyzed direct arylation of 1 aryl 1h Imidazoles
Journal of Organic Chemistry, 2005Co-Authors: Fabio Bellina, Silvia Cauteruccio, Luisa Mannina, Renzo Rossi, S VielAbstract:A variety of 1,5-diaryl-1H-Imidazoles have been regioselectively synthesized by direct coupling of 1-aryl-1H-Imidazoles with aryl iodides or bromides in DMF in the presence of CsF as the base and a catalyst precursor consisting of a mixture of Pd(OAc)2 and AsPh3. The data obtained in this synthetic study support a reaction mechanism involving an electrophilic attack of an arylpalladium(II) halide species onto the imidazole ring. Interestingly, some imidazole derivatives synthesized in this study have been found to exhibit significant cytotoxic activity against human tumor cell lines.
Tiny J P Adolfs - One of the best experts on this subject based on the ideXlab platform.
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bioisosteric replacements of the pyrazole moiety of rimonabant synthesis biological properties and molecular modeling investigations of thiazoles triazoles and Imidazoles as potent and selective cb1 cannabinoid receptor antagonists
Journal of Medicinal Chemistry, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C Mccreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter De LooffAbstract:Series of thiazoles, triazoles, and Imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB1 receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The thiazoles, triazoles, and Imidazoles elicited in vitroCB1 antagonistic activities and in general exhibited considerable CB1 vs CB2 receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure−activity relationship (SAR) study revealed a close correlation between the biological results in the imidazo...
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bioisosteric replacements of the pyrazole moiety of rimonabant synthesis biological properties and molecular modeling investigations of thiazoles triazoles and Imidazoles as potent and selective cb1 cannabinoid receptor antagonists
Journal of Medicinal Chemistry, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C Mccreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter De LooffAbstract:Series of thiazoles, triazoles, and Imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and Imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.