RESUMO
Studies examining the effects of feeding lipid oxidation products (LOPs) to pigs on pork quality and storage stability have mostly focused on refrigerated storage and produced mixed results. We investigated the effects of adding yellow grease, containing commercially relevant levels of LOPs, to swine diets on quality and storage stability of ground salted pork. Twenty-four domestic pigs were divided into three study groups and fed the following diet regimens for five months: (1) Standard Diet (STD), (2) STDâ¯+â¯yellow grease (YG, high LOPs), or (3) STDâ¯+â¯corn oil (CO, negligible LOPs). Post-harvest carcass characteristics and the effects of frozen and refrigerated storage on color and lipid oxidation of salted pork patties were studied. While feeding of yellow grease had no impact on color, it increased the susceptibility of pork patties to lipid oxidation during storage (186% and 73% higher accumulation of LOPs in patties from pigs fed STDâ¯+â¯YG when compared to those fed STD and STDâ¯+â¯CO, respectively).
Assuntos
Ração Animal/análise , Armazenamento de Alimentos , Produtos da Carne/análise , Carne de Porco/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Feminino , Metabolismo dos Lipídeos , Peroxidação de Lipídeos , Masculino , Oxirredução , Sus scrofa/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Indenos/síntese química , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/síntese química , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Desenho de Fármacos , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transtornos Parkinsonianos/induzido quimicamente , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Efts and adult specimens (n = 142) of the red-spotted newt Notophthalmus viridescens from various locations in Canada and USA were analyzed for the presence of tetrodotoxin (TTX) and of its analogues 6-epitetrodotoxin and 11-oxotetrodotoxin. Considerable individual variations in toxin levels were found within and among populations from New Hampshire, New York, Pennsylvania, and Virginia ranging from non-detectable to 69 µg TTX per g newt. TTX and its analogues were absent in efts and adults from various locations in the Canadian province Nova Scotia, the northernmost distribution of the newt, and in adults from Florida. Newts kept in captivity for several years and reared on toxin-free diet lost their toxicity. Bayesian and maximum likelihood phylogenetic analysis of specimens from the various populations using three phylogenetic markers (COI, ND2 and 16S RNA) revealed that populations from the northern states of the USA and Canada are genetically homogenous, whereas the newts from Florida exhibited a much higher level of genetic divergence. An exogenous source of TTX in the newts either via the food chain or by synthesis of symbiotic bacteria is suggested to explain the high variability and lack of TTX in certain populations.
Assuntos
Notophthalmus viridescens , Tetrodotoxina/análogos & derivados , Animais , Teorema de Bayes , DNA/genética , DNA/isolamento & purificação , Florida , New Hampshire , New York , Nova Escócia , Pennsylvania , Filogenia , Filogeografia , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/isolamento & purificação , Análise de Sequência de DNA , Manejo de Espécimes , Tetrodotoxina/análise , VirginiaRESUMO
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antiparkinsonianos/síntese química , Indenos/síntese química , Doença de Parkinson/metabolismo , Pirimidinas/síntese química , Receptor A2A de Adenosina/fisiologia , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Callithrix , Modelos Animais de Doenças , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Neurotransmissores/química , Pirimidinas/química , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Aminas/química , Neurotransmissores/química , Pirimidinas/química , Aminas/síntese química , Aminas/uso terapêutico , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Pós-Menopausa/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Benzopiranos/síntese química , Benzopiranos/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Linhagem Celular Tumoral , Colesterol/sangue , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Fogachos/tratamento farmacológico , Humanos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Pós-Menopausa/sangue , Ratos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Relação Estrutura-Atividade , Especificidade por Substrato , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/metabolismoRESUMO
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.
Assuntos
Glicolatos/síntese química , Glicolatos/farmacologia , PPAR delta/agonistas , Técnicas de Química Combinatória , Desenho de Fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Glicolatos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
The deposition of chemical pollutants into roadside wetlands from runoff is a current environmental concern. In northern latitudes, a major pollutant in runoff water is salt (NaCl), used as de-icing agents. In this study, 26 roadside ponds were surveyed for amphibian species richness and chloride concentration. Acute toxicity tests (LC(50)) were performed on five locally common amphibian species using a range of environmentally significant NaCl concentrations. Field surveys indicated that spotted salamanders (Ambystoma maculatum) and wood frogs (Rana sylvatica) did not occupy high chloride ponds. American toads (Bufo americanus) showed no pond preference based on chloride concentration. Acute toxicity tests showed spotted salamanders and wood frogs were most sensitive to chloride, and American toads were the least. Spring peepers (Pseudacris crucifer) and green frogs (Rana clamitans) showed intermediate sensitivities. We concluded that chloride concentrations in ponds due to application of de-icing salts, influenced community structure by excluding salt intolerant species.
Assuntos
Anfíbios/fisiologia , Ecossistema , Cloreto de Sódio/toxicidade , Poluentes Químicos da Água/toxicidade , Ambystoma/fisiologia , Animais , Bufonidae/fisiologia , Cloretos/toxicidade , Água Doce , Nova Escócia , Ranidae/fisiologia , Testes de Toxicidade Aguda , Movimentos da ÁguaRESUMO
The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.
Assuntos
Cério/química , Césio/química , Cloretos/química , Compostos de Lítio/química , Nitrilas/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ultrassom , Benzeno/química , Estrutura Molecular , Nitrilas/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.
Assuntos
PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazóis/química , Tiadiazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Camundongos , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Ativação TranscricionalRESUMO
Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.
Assuntos
Hipolipemiantes/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazóis/síntese química , Administração Oral , Animais , Apolipoproteína A-I/genética , Linhagem Celular , Feminino , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologiaRESUMO
Through an in vivo screening model, we developed the in vivo SAR of beta-alkylthio indolyl carbinols. Through these efforts we identified a compound with potent oral in vivo efficacy in both immature and mature rat prostate weight reduction models and in a murine xenograft prostate cancer model.
Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Antineoplásicos/síntese química , Química Farmacêutica/métodos , Indóis/síntese química , Metanol/análogos & derivados , Metanol/química , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/farmacologia , Masculino , Camundongos , Transplante de Neoplasias , Ratos , Relação Estrutura-AtividadeRESUMO
Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.