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1.
J Med Chem ; 57(1): 159-70, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24359185

RESUMO

A series of novel, potent, and selective human ß2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no ß2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Sulfonas/síntese química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Esquema de Medicação , Descoberta de Drogas , Cobaias , Hepatócitos/metabolismo , Humanos , Ratos , Sulfonas/metabolismo , Sulfonas/farmacologia , Traqueia/efeitos dos fármacos
2.
Drug Discov Today ; 18(23-24): 1158-72, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24051399

RESUMO

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.


Assuntos
Química Farmacêutica/educação , Desenho de Fármacos , Descoberta de Drogas/métodos , Currículo , Indústria Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Inibidores de Fosfoinositídeo-3 Quinase , Solubilidade
4.
Nucleic Acids Res ; 36(21): e142, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18927103

RESUMO

Previous research demonstrated the use of evolutionary computation for the discovery of transcription factor binding sites (TFBS) in promoter regions upstream of coexpressed genes. However, it remained unclear whether or not composite TFBS elements, commonly found in higher organisms where two or more TFBSs form functional complexes, could also be identified by using this approach. Here, we present an important refinement of our previous algorithm and test the identification of composite elements using NFAT/AP-1 as an example. We demonstrate that by using appropriate existing parameters such as window size, novel-scoring methods such as central bonusing and methods of self-adaptation to automatically adjust the variation operators during the evolutionary search, TFBSs of different sizes and complexity can be identified as top solutions. Some of these solutions have known experimental relationships with NFAT/AP-1. We also indicate that even after properly tuning the model parameters, the choice of the appropriate window size has a significant effect on algorithm performance. We believe that this improved algorithm will greatly augment TFBS discovery.


Assuntos
Algoritmos , Elementos Reguladores de Transcrição , Fatores de Transcrição/metabolismo , Sítios de Ligação , Biologia Computacional , Evolução Molecular , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fator 1 de Transcrição de Octâmero/metabolismo , Fator de Transcrição AP-1/metabolismo
5.
Biosystems ; 81(2): 137-54, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15941617

RESUMO

Transcription factors are key regulatory elements that control gene expression. The TRANSFAC database represents the largest repository for experimentally derived transcription factor binding sites (TFBS). Understanding TFBS, which are typically conserved during evolution, helps us identify genomic regions related to human health and disease, and regions that might be predictive of patient outcomes. Here we present a statistical analysis of all TFBS in the TRANSFAC database. Our analysis suggests that current definition of TFBS core regions in TRANSFAC should be re-examined so as to capture a more precise notion of "cores." We offer insight into more appropriate definitions of TFBS consensus sequences and core regions. These revised definitions provide a better understanding of the nature of transcription factor-DNA binding and assist with developing algorithms for de novo TFBS discovery as well as finding novel variants of known TFBS.


Assuntos
Bases de Dados de Proteínas , Fatores de Transcrição/química , Algoritmos , Motivos de Aminoácidos , Animais , Sítios de Ligação , Análise por Conglomerados , Biologia Computacional/métodos , Regulação da Expressão Gênica , Humanos , Modelos Estatísticos , Software , Estatística como Assunto , Biologia de Sistemas , Transcrição Gênica
7.
Environ Pollut ; 133(1): 5-9, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15327850

RESUMO

The paper discusses key aspects of the European Union (EU) regulatory policy related to the persistence and bound residues of agricultural pesticide active substances in soil. This is examined in the context of the EU Authorisations Directive (91/414/EEC) which will gradually replace existing national systems of agricultural pesticide regulation within EU Member States. Discussion is concentrated on this directive, looking in particular at the Uniform Principles therein and the possible ways that these decision-making guidelines could be developed into a regulatory framework. The aim in this process of negotiated development is to identify any questions or data requirements that will be needed for persistent pesticides or soil bound residues, over and above those generally required for all compounds. The present EU regulatory position on soil non-extractable or bound residues is examined and possible future improvements to the system are described and discussed.


Assuntos
Poluição Ambiental , Resíduos de Praguicidas , Poluentes do Solo , Agricultura , Disponibilidade Biológica , Monitoramento Ambiental/métodos , Poluição Ambiental/legislação & jurisprudência , União Europeia , Praguicidas , Solo , Fatores de Tempo
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