RESUMEN
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.
Asunto(s)
Benzodiazepinonas/química , Técnicas Químicas Combinatorias , Estructura Molecular , Fenómenos Químicos Orgánicos , EstereoisomerismoRESUMEN
We herein document the first example of a reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions. The combined use of two polymer-supported reagents (polystyrene-1,5,7-triazabicyclo[4,4,0]dec-5-ene/Cu and polystyrene-2-iodoxybenzamide) overcomes the thermodynamic instability of copper(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu(I)-catalyzed alkyne-azide cycloaddition.
Asunto(s)
Alquinos/química , Azidas/química , Cobre/química , Poliestirenos/química , Triazoles/síntesis química , Catálisis , Ciclización , Estructura Molecular , Oxidación-Reducción , Termodinámica , Triazoles/químicaRESUMEN
An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2(1H)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner.
Asunto(s)
Pirazinas/síntesis química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Ciclización , Descubrimiento de Drogas , Estructura Molecular , Pirazinas/química , EstereoisomerismoRESUMEN
The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
Asunto(s)
Halogenación , Antagonistas de Receptores Purinérgicos P1 , Cricetinae , Animales , Humanos , Células CHO , Leucocitos Mononucleares/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacología , Receptor de Adenosina A2B/metabolismo , Ligandos , HalógenosRESUMEN
We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure-activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38 Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Pirimidinas/farmacología , Receptor de Adenosina A2B/efectos de los fármacos , Antagonistas del Receptor de Adenosina A2/metabolismo , Animales , Células CHO , Cricetulus , AMP Cíclico/metabolismo , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Metástasis de la Neoplasia/prevención & control , Pirimidinas/química , Pirimidinas/metabolismo , Ensayo de Unión Radioligante , Receptor de Adenosina A2B/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas del Receptor de Adenosina A3 , Técnicas Químicas Combinatorias/métodos , Pirimidinas/síntesis química , Humanos , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Receptor de Adenosina A3/metabolismoRESUMEN
Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Descubrimiento de Drogas , Pirimidinonas/farmacología , Receptor de Adenosina A2B/metabolismo , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
An expedient and concise Ugi-based unified approach for the rapid assembly of quinoxaline frameworks has been developed. This convergent and versatile method uses readily available commercial reagents, does not require advanced intermediates, and exhibits excellent bond-forming efficiency, thus exemplifying the operationally simple synthesis of quinoxaline libraries.
Asunto(s)
Quinoxalinas/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Técnicas Químicas Combinatorias/economía , Técnicas Químicas Combinatorias/métodos , Quinoxalinas/química , Bibliotecas de Moléculas Pequeñas/química , Factores de TiempoRESUMEN
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.
Asunto(s)
Nitrilos/síntesis química , Pirimidinas/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Técnicas Químicas Combinatorias , Nitrilos/química , Pirimidinas/química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
We describe the discovery and optimization of 3,4-dihydropyrimidin-2(1H)-ones as a novel family of (nonxanthine) A2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure-activity and structure-selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA2B AdoR affinity and remarkable selectivity profiles.
RESUMEN
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.
Asunto(s)
Acetamidas/síntesis química , Antagonistas del Receptor de Adenosina A3/química , Anisoles/síntesis química , Simulación por Computador , Pirimidinas/síntesis química , Acetamidas/química , Anisoles/química , Sitios de Unión , Humanos , Modelos Moleculares , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Dioxanos/farmacología , Descubrimiento de Drogas , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Dioxanos/síntesis química , Dioxanos/química , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Relación Estructura-ActividadRESUMEN
An efficient solution-phase parallel procedure to perform the structural diversification of some formyl-nitrogen heterocycles (A) using the reusable TBD supported base is described. The library synthesis is based in a consecutive Alkylation-Knoevenagel functionalisation that uses alkyl halides (B), Michael acceptors (C) and activated methylene compounds (D) as diversity elements.
Asunto(s)
Compuestos Aza/síntesis química , Compuestos de Azabiciclo/química , Compuestos Heterocíclicos/síntesis química , Alquilación , Compuestos Aza/química , Compuestos Heterocíclicos/química , Ensayos Analíticos de Alto Rendimiento , Estructura Molecular , Soluciones , EstereoisomerismoRESUMEN
A solution phase protocol that enabled the synthesis of three diverse libraries of pyridazin-3-ones incorporating α,ß-unsaturated moieties at position 5 of the heterocyclic core has been developed using silica-supported aluminum trichloride as a heterogeneous and reusable catalyst. This robust procedure has facilitated the hit to lead process for these series of compounds and allowed the identification of new potent derivatives that elicit antiplatelet activity in the low micromolar range.