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1.
J Med Chem ; 65(3): 2091-2106, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35068155

RESUMO

We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.


Assuntos
Antagonistas do Receptor A1 de Adenosina/química , Pirimidinas/química , Antagonistas do Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Sítios de Ligação , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Cinética , Simulação de Acoplamento Molecular , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Receptor A1 de Adenosina/química , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-Atividade
2.
J Med Chem ; 64(1): 458-480, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33372800

RESUMO

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.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Pirimidinas/farmacologia , Receptor A2B de Adenosina/efeitos dos fármacos , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Células CHO , Cricetulus , AMP Cíclico/metabolismo , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Metástase Neoplásica/prevenção & controle , Pirimidinas/química , Pirimidinas/metabolismo , Ensaio Radioligante , Receptor A2B de Adenosina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
3.
J Dairy Sci ; 103(10): 8808-8821, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32828516

RESUMO

This work aimed to establish the ultrasound parameters that can be useful to classify the defects in the soft cheese Torta del Casar during ripening. During ripening by ultrasound, 1 standard and 3 defective cheese batches (anomalous microbial population, inadequate pressing curd, and excessive pressing curd) were evaluated. Ultrasound parameters related to velocity, attenuation, and frequency were calculated and correlated with the physicochemical and rheological properties of the cheeses. Ultrasound data were considered variables in linear discriminant analysis to attempt cheese classification at different periods of the ripening process. Defective soft cheeses could be discriminated from standard ones with good accuracy, mainly at the final stages of ripening. The differentiation of cheese samples from 2 of the defective cheese batches (anomalous microbial population and inadequate pressing curd) from the standard was mainly attributed to different values of the attenuation-related parameters, whereas for samples from the other defective batch (excessive pressing curd), some parameters related to velocity and frequency were responsible for such discrimination.


Assuntos
Queijo , Manipulação de Alimentos , Animais , Queijo/análise , Queijo/microbiologia , Controle de Qualidade , Ultrassonografia
4.
Ultrasonics ; 76: 192-199, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110138

RESUMO

Ultrasound evaluation permits the state of milk being curdled to be determined quickly and cheaply, thus satisfying the demands faced by today's dairy product producers. This paper describes the non-invasive ultrasonic method of in situ monitoring the changing physical properties of milk during the renneting process. The basic objectives of the study were, on the one hand, to confirm the usefulness of conventional non-destructive ultrasonic testing (time-of-flight and attenuation of the ultrasound waves) in monitoring the process in the case of ewe's milk, and, on the other, to include other ultrasound parameters which have not previously been considered in studies on this topic, in particular, parameters provided by the Fast Fourier Transform technique. The experimental study was carried out in a dairy industry environment on four 52-l samples of raw milk in which were immersed 500kHz ultrasound transducers. Other physicochemical parameters of the raw milk (pH, dry matter, protein, Gerber fat test, and lactose) were measured, as also were the pH and temperature of the curdled samples simultaneously with the ultrasound tests. Another contribution of this study is the linear correlation analysis of the aforementioned ultrasound parameters and the physicochemical properties of the curdled milk.


Assuntos
Proteínas do Leite/metabolismo , Leite , Ultrassonografia/métodos , Animais , Indústria de Laticínios , Análise de Fourier , Carneiro Doméstico , Ultrassonografia/instrumentação
5.
J Med Chem ; 59(5): 1967-83, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26824742

RESUMO

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.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Descoberta de Drogas , Pirimidinonas/farmacologia , Receptor A2B de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade
6.
ACS Comb Sci ; 15(7): 370-8, 2013 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-23697392

RESUMO

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/química
7.
ACS Med Chem Lett ; 4(11): 1031-6, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24900602

RESUMO

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.

8.
Org Biomol Chem ; 9(2): 351-7, 2011 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-21049105

RESUMO

A convergent and versatile Vilsmeier-Haack-based carbo-annulation strategy that exhibits an unusually elevated bond-forming efficiency has been developed. By virtue of its innovative approach, structure economy and simple execution conditions the methodology reported here constitutes a very attractive protocol that enables the rapid assembly of structurally diverse quinazoline chemotypes.


Assuntos
Quinazolinas/química , Alcaloides/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular
9.
Comb Chem High Throughput Screen ; 11(10): 843-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19075606

RESUMO

Several applications of polystyrene-supported 1,1,3,3-tetramethylguanidine (PS-TMG) in synthetic organic chemistry have been explored. This study evidenced the effectiveness and versatility of this new member of the supported guanidine superbases as an attractive candidate to replace the bases usually employed in organic synthesis during the implementation of environmentally friendly preparative processes.


Assuntos
Guanidinas/química , Guanidinas/síntese química , Poliestirenos/química , Amidas/química , Catálise , Ésteres/química , Estrutura Molecular
10.
Bioorg Med Chem Lett ; 16(4): 1080-3, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16290144

RESUMO

As part of the optimization process of the lead compound I a focussed library of diversely substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl or 3-phenylprop-2-enoyl fragment at position 5 has been obtained and evaluated as antiplatelet agents. The structural modification at positions 2, 6 and 4 of the heterocyclic moiety allowed us to obtain preliminary information on the structure-activity relationship in this family.


Assuntos
Inibidores da Agregação Plaquetária/síntese química , Agregação Plaquetária/efeitos dos fármacos , Piridazinas/síntese química , Piridazinas/farmacologia , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Piridazinas/química , Estereoisomerismo , Relação Estrutura-Atividade
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