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1.
J Agric Food Chem ; 67(22): 6133-6142, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31067046

RESUMO

Glyphosate-based herbicide (GBH) applications were reported to induce physiological damages to glyphosate-resistant (GR) soybean, which were mainly attributed to aminomethylphosphonic acid (AMPA). In order to study glyphosate and AMPA dynamics in plants and associated phytotoxic effects, a greenhouse experiment was set where GR soybeans were exposed to GBH (0.7 to 4.5 kg glyphosate ha-1) and sampled over time (2, 7, 14, and 28 days after treatment (DAT)). Hydrogen peroxide content increased 2 DAT, while a decrease was observed for the effective quantum yield (2, 7, 14 DAT), stomatal conductance (2 DAT), and biomass (14 DAT). Glyphosate content was higher in leaves, followed by stems, and then roots. AMPA content tended to increase with time, especially in roots, and the amount of AMPA in roots was negatively correlated to mostly all phytotoxicity indicators. This finding is important since AMPA residues are measured in agricultural soils several months after GBH applications, which could impact productivity in GR crops.


Assuntos
Glycine max/química , Glicina/análogos & derivados , Resistência a Herbicidas , Herbicidas/análise , Compostos Organofosforados/análise , Glicina/análise , Glicina/metabolismo , Glicina/farmacologia , Herbicidas/metabolismo , Herbicidas/farmacologia , Compostos Organofosforados/metabolismo , Folhas de Planta/química , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Caules de Planta/química , Caules de Planta/efeitos dos fármacos , Caules de Planta/metabolismo , Glycine max/efeitos dos fármacos , Glycine max/metabolismo , Glifosato
2.
Bioorg Med Chem Lett ; 24(3): 917-22, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24412110

RESUMO

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Farmacorresistência Viral/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Células Cultivadas , Cristalografia por Raios X , Cães , HIV-1/genética , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Mutação , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/química
3.
J Med Chem ; 53(5): 2227-38, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20163116

RESUMO

The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.


Assuntos
Analgésicos/síntese química , Benzoatos/síntese química , Ciclopropanos/síntese química , Antagonistas de Prostaglandina/síntese química , Receptores de Prostaglandina E/metabolismo , Tiofenos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzoatos/química , Benzoatos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Dor/tratamento farmacológico , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacocinética
4.
ACS Med Chem Lett ; 1(4): 170-4, 2010 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900191

RESUMO

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

5.
J Vet Intern Med ; 20(1): 175-81, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16496938

RESUMO

Phosphodiesterase-4 (PDE 4) enzyme inhibitors have been shown to have anti-inflammatory properties in various animal disease processes and therefore could be effective drugs for the treatment of equine airway diseases. The purpose of this study was to evaluate the efficacy and adverse effects of the PDE 4 inhibitor L-826,141 in horses with heaves. In a blinded parallel design, horses with heaves exposed daily to moldy hay were given a placebo for 14 days and then administered either L-826,141 (n = 6; loading dose of 1 mg/kg IV followed by 0.5 mg/kg IV q48h) or dexamethasone (n = 6; 0.04 mg/kg IV q24h) from days 15 to 29 (study 1). Pulmonary function and bronchoalveolar (BAL) cytology were evaluated weekly from baseline (day 0) to 29 days. In study 2, horses were treated with L-826,141 (1.0 mg/kg IV q24h) for 8 days. Although ex vivo lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha and LTB4 production by fresh blood were inhibited up to 90% after repeated administrations of L-826,141, this treatment failed to improve lung function. In contrast, dexamethasone (positive control) treatment resulted in significant improvement in lung mechanics and airway function in all horses. Neither drug had a significant effect on BAL total cell counts and differential cytology. Administration of the PDE 4 inhibitor L-826,141 for up to 14 days to horses with heaves was not associated with an improvement in airway function or inflammation. These findings suggest that the PDE 4 enzyme is not a key mediator of lung inflammation in heaves.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Doenças dos Cavalos/tratamento farmacológico , Pneumopatias Obstrutivas/veterinária , Piridinas/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Cavalos , Leucotrieno B4/metabolismo , Pneumopatias Obstrutivas/tratamento farmacológico , Pneumopatias Obstrutivas/metabolismo , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
6.
Bioorg Med Chem Lett ; 15(4): 1155-60, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15686932

RESUMO

The synthesis and the EP(1) receptor binding affinity of 2,3-diarylthiophene derivatives are described. The evaluation of the structure-activity relationship (SAR) in this series led to the identification of compounds 4, 7, and 12a, which exhibit high affinity for the human EP(1) receptor and a selectivity greater than 100-fold against the EP(2), EP(3), EP(4), DP, FP, and IP receptors and greater than 25-fold versus the TP receptor. These three antagonists present good pharmacokinetics in rats and significant differences in the way they are distributed in the brain.


Assuntos
Receptores de Prostaglandina E/antagonistas & inibidores , Tiofenos/síntese química , Tiofenos/farmacocinética , Animais , Encéfalo/metabolismo , Linhagem Celular , Meia-Vida , Humanos , Farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-Atividade , Tiofenos/farmacologia , Distribuição Tecidual
7.
J Med Chem ; 46(12): 2413-26, 2003 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-12773045

RESUMO

A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Álcoois/síntese química , Óxidos N-Cíclicos/síntese química , Inibidores de Fosfodiesterase/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Piridinas/síntese química , Álcoois/farmacocinética , Álcoois/farmacologia , Álcoois/toxicidade , Animais , Broncoconstrição/efeitos dos fármacos , Cristalografia por Raios X , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cães , Canal de Potássio ERG1 , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go , Cobaias , Humanos , Técnicas In Vitro , Síndrome do QT Longo/induzido quimicamente , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/toxicidade , Ligação Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/toxicidade , Ratos , Saimiri , Ovinos , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamente
8.
Bioorg Med Chem Lett ; 13(11): 1923-6, 2003 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-12749899

RESUMO

The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Picolinas/química , Picolinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Meia-Vida , Humanos , Concentração Inibidora 50 , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Picolinas/síntese química , Picolinas/farmacocinética , Ratos , Saimiri , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
9.
Bioorg Med Chem Lett ; 13(4): 741-4, 2003 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-12639571

RESUMO

The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue. The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 microM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2)=2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv).


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Aminopiridinas/farmacocinética , Animais , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Furões , Cobaias , Meia-Vida , Humanos , Concentração Inibidora 50 , Ratos , Ovinos , Relação Estrutura-Atividade , Equivalência Terapêutica , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vômito/induzido quimicamente
10.
Bioorg Med Chem Lett ; 12(20): 3009-13, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12270195

RESUMO

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Alquilação , Animais , Disponibilidade Biológica , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Meia-Vida , Humanos , Indicadores e Reagentes , Inibidores de Fosfodiesterase/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/síntese química , Fator de Necrose Tumoral alfa/farmacologia
11.
Bioorg Med Chem Lett ; 12(16): 2149-52, 2002 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-12127525

RESUMO

A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Catecóis/química , Piridinas/química , Piridinas/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Piridinas/metabolismo , Ratos , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 12(11): 1457-61, 2002 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-12031319

RESUMO

Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Linhagem Celular Transformada/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Eméticos/farmacologia , Furões , Cobaias , Meia-Vida , Humanos , Concentração Inibidora 50 , Ovalbumina/farmacologia , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacocinética , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Saimiri , Ovinos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
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