RESUMO
A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.
Assuntos
Benzodiazepinonas/química , Técnicas de Química Combinatória , Estrutura Molecular , Fenômenos de Química Orgânica , EstereoisomerismoRESUMO
A practical and divergent solution-phase synthetic strategy has been optimized to prepare a highly diverse library of 2,4-diaryl- and 2,6-diarylpyrimidines. Structural elaboration of the starting heterocyclic scaffolds was accomplished by exploiting the potential for diversity offered by the Suzuki-Miyaura cross-coupling reaction. These studies enabled the identification of structurally simple, highly potent, and selective A(3) adenosine receptor antagonists.
Assuntos
Antagonistas do Receptor A3 de Adenosina , Técnicas de Química Combinatória/métodos , Pirimidinas/síntese química , Humanos , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Receptor A3 de Adenosina/metabolismoRESUMO
We report the first family of 2-acetamidopyridines as potent and selective A3 adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (Ki < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA3AR, and exemplifies the benefits of a joint theoretical-experimental approach to identify novel hA3AR antagonists through succinct and efficient synthetic methodologies.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Antagonistas do Receptor A3 de Adenosina/química , Antagonistas do Receptor A3 de Adenosina/farmacologia , Receptor A3 de Adenosina/metabolismo , Animais , Sítios de Ligação , Células CHO , Desenho Assistido por Computador , Cricetulus , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Nitrogênio/química , Nitrogênio/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptor A3 de Adenosina/química , Relação Estrutura-AtividadeRESUMO
An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.
Assuntos
Nitrilas/síntese química , Pirimidinas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Técnicas de Química Combinatória , Nitrilas/química , Pirimidinas/química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A(3) adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K(i) on A(3) AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A(3)AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure-activity and structure-selectivity relationships in this series.
Assuntos
Acetamidas/síntese química , Antagonistas do Receptor A3 de Adenosina/química , Anisóis/síntese química , Simulação por Computador , Pirimidinas/síntese química , Acetamidas/química , Anisóis/química , Sítios de Ligação , Humanos , Modelos Moleculares , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
We herein document the discovery of 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones as a novel family of platelet aggregation inhibitors. The preliminary optimization study enabled us to establish the most salient features of the structure-activity relationships in this series as well as to identify novel derivatives that are upto 60 times more potent than the hit structure 1 and slightly superior to the reference drug Milrinone.
Assuntos
Dioxanos/farmacologia , Descoberta de Drogas , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Dioxanos/síntese química , Dioxanos/química , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Relação Estrutura-AtividadeRESUMO
Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor. The robustness of the computational model was subsequently evaluated by the design of new derivatives exploring the alkyl substituent of the exocyclic amide group. The synthesis and evaluation of the novel compounds validated the predictive power of the model, exhibiting excellent agreement between predicted and experimental activities.