Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chemistry ; 23(33): 7887-7890, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28378374

RESUMO

The study of noncovalent interactions, notably including drug-protein binding, relies heavily on the language of localized functional group contacts: hydrogen bonding, π-π interactions, CH-π contacts, halogen bonding, etc. Applying the state-of-the-art functional group symmetry-adapted perturbation theory (F-SAPT) to an important question of chloro versus methyl aryl substitution in factor Xa inhibitor drugs, we find that a localized contact model provides an incorrect picture for the origin of the enhancement of chloro-containing ligands. Instead, the enhancement is found to originate from many intermediate-range contacts distributed throughout the binding pocket, particularly including the peptide bonds in the protein backbone. The contributions from these contacts are primarily electrostatic in nature, but require ab initio computations involving nearly the full drug-protein pocket system to be accurately quantified.


Assuntos
Inibidores do Fator Xa/metabolismo , Fator Xa/metabolismo , Cristalografia por Raios X , Fator Xa/química , Inibidores do Fator Xa/química , Ligações de Hidrogênio , Ligantes , Conformação Molecular , Ligação Proteica , Teoria Quântica , Eletricidade Estática , Termodinâmica
2.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112924

RESUMO

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.


Assuntos
Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas-G/metabolismo
3.
J Med Chem ; 56(23): 9586-600, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24182233

RESUMO

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.


Assuntos
Piridazinas/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Triazóis/farmacocinética , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Meia-Vida , Ligação Proteica , Piridazinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/química
4.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22650305

RESUMO

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese química
5.
Eur J Pharmacol ; 651(1-3): 9-17, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21044623

RESUMO

The cannabinoid CB(1) G protein-coupled receptor has been shown to be a regulator of food consumption and has been studied extensively as a drug target for the treatment of obesity. To advance understanding of the receptor's three-dimensional structure, we performed mutagenesis studies at human cannabinoid CB(1) receptor residues F200 and S383 and measured changes in activity and binding affinity of compounds from two recently discovered active chemotypes, arylsulfonamide agonists and tetrahydroquinoline-based inverse agonists, as well as literature compounds. Our results add support to previous findings that both agonists and inverse agonists show varied patterns of binding at the two mutated residue sites, suggesting multiple subsites for binding to the cannabinoid CB(1) receptor for both functional types of ligands. We additionally find that an F200L mutation in the receptor largely restores binding affinity to ligands and significantly decreases constitutive activity when compared to F200A, resulting in a receptor phenotype that is closer to the wild-type receptor. The results downplay the importance of aromatic stacking interactions at F200 and suggest that a bulky hydrophobic contact is largely sufficient to provide significant receptor function and binding affinity to cannabinoid CB(1) receptor ligands.


Assuntos
Mutagênese , Fenilalanina , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Serina , Animais , Benzoatos/metabolismo , Benzoatos/farmacologia , Células CHO , Cricetinae , Cricetulus , Agonismo Inverso de Drogas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Fenilalanina/genética , Fenilalanina/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/genética , Serina/genética , Serina/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia
6.
Bioorg Med Chem Lett ; 15(18): 3992-5, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16046120

RESUMO

Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Nitrilos/farmacologia , Inibidores de Proteases/farmacologia , Sítios de Ligação , Ciclização , Dipeptidil Peptidase 4/química , Modelos Moleculares , Estrutura Molecular , Nitrilos/química , Inibidores de Proteases/química , Estrutura Terciária de Proteína
7.
J Med Chem ; 47(10): 2587-98, 2004 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-15115400

RESUMO

A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.


Assuntos
Ciclopropanos/síntese química , Dipeptidil Peptidase 4/metabolismo , Inibidores Enzimáticos/síntese química , Nitrilos/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Animais , Simulação por Computador , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Dipeptídeos/química , Dipeptidil Peptidase 4/química , Estabilidade de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Nitrilos/química , Nitrilos/farmacologia , Prolina/química , Prolina/farmacologia , Ratos , Ratos Zucker , Soluções
8.
J Mol Graph Model ; 22(1): 31-40, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12798389

RESUMO

An important element of any structure-based virtual screening (SVS) technique is the method used to orient the ligands in the target active site. This has been a somewhat overlooked issue in recent SVS validation studies, with the assumption being made that the performance of an algorithm for a given set of orientation sampling settings will be representative for the general behavior of said technique. Here, we analyze five different SVS targets using a variety of sampling paradigms within the DOCK, GOLD and PROMETHEUS programs over a data set of approximately 10,000 noise compounds, combined with data sets containing multiple active compounds. These sets have been broken down by chemotype, with chemotype hit rate used to provide a measure of enrichment with a potentially improved relevance to real world SVS experiments. The variability in enrichment results produced by different sampling paradigms is illustrated, as is the utility of using pharmacophores to constrain sampling to regions that reflect known structural biology. The difference in results when comparing chemotype with compound hit rates is also highlighted.


Assuntos
Simulação por Computador , Desenho de Drogas , Ligantes , Modelos Moleculares , Software , Sítios de Ligação , Biologia Computacional , Gráficos por Computador , Bases de Dados de Proteínas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/fisiologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiologia , Serina Endopeptidases/metabolismo , Serina Endopeptidases/fisiologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA