RESUMEN
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hígado/efectos de los fármacos , Pirrolidinas/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células Hep G2 , Humanos , Hígado/enzimología , Hígado/metabolismo , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Estearoil-CoA Desaturasa/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.
Asunto(s)
Bencimidazoles/química , Inhibidores Enzimáticos/química , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Nitrilos/química , Fenantrenos/química , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Cobayas , Humanos , Hiperalgesia/tratamiento farmacológico , Oxidorreductasas Intramoleculares/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacocinética , Fenantrenos/síntesis química , Fenantrenos/farmacocinética , Prostaglandina-E Sintasas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
OBJETIVO: Comparar o ganho pôndero-estatural e a frequência de complicações clínicas em recém-nascidos pré-termo com peso inferior a 1.500 g, alimentados exclusivamente com leite humano cru da própria mãe com e sem aditivo até atingirem o peso de 1.800 g. MÉTODOS: Ensaio clínico prospectivo randomizado duplo-cego em 40 recém-nascidos pré-termo com peso de nascimento < 1.500 g e ≤ 34 semanas, internados em unidade de terapia intensiva neonatal no período de agosto de 2005 a abril de 2007. Foram randomizados em 2 grupos: controle (leite humano puro) e intervenção (leite humano com aditivo). A fortificação foi feita no leite humano cru ordenhado no momento da oferta, quando a dieta atingiu 100 mL/kg/dia (até os neonatos atingirem peso de 1.800 g). Foram comparados ganho de peso diário, crescimento e perímetro cefálico semanalmente, variáveis nutricionais e complicações clínicas. RESULTADOS: A fortificação resultou em melhor crescimento, com ganho de 1,09 e 0,87 cm/semana (p = 0,003) e perímetro cefálico observado de 0,73 e 1,02 cm/semana (p = 0,0001), respectivamente grupo intervenção e controle. O ganho de peso foi de 24,4 e 21,2 g/dia (p = 0,075). Quanto às complicações clínicas observadas, não houve diferença significante. CONCLUSÕES: O uso de aditivo no leite humano cru da própria mãe proporcionou melhor crescimento, com aumento significativo do comprimento e do perímetro cefálico.
OBJECTIVE: To compare the weight and height gain and the frequency of clinical complications in preterm newborns weighing less than 1,500 g, exclusively fed human milk or fortified human milk until reaching 1,800 g. METHODS: Prospective double-blind randomized controlled trial involving 40 preterm infants weighing < 1,500 g at birth and ≤ 34 weeks of gestational age, admitted to a neonatal intensive care unit from August 2005 to April 2007. Preterm infants were randomized into two groups: control (human milk) and intervention (fortified human milk). Fortifiers were added to manually expressed human milk when feeding volume reached 100 mL/kg/day until newborns reached 1,800 g. Daily weight gain, weekly length and head circumference gain, nutritional variables and clinical complications were compared. RESULTS: Human milk fortification resulted in better growth, with length gain of 1.09 and 0.87 cm/week (p = 0.003) and head circumference gain of 0.73 and 1.02 cm/week (p = 0.0001), respectively, for intervention and control groups. The weight gain was 24.4 and 21.1 g/day (p = 0.075). There were no significant clinical complications. CONCLUSIONS: Human milk fortification resulted in better growth, significant increase in length and head circumference.
Asunto(s)
Femenino , Humanos , Recién Nacido , Masculino , Alimentos Fortificados , Recien Nacido Prematuro/crecimiento & desarrollo , Recién Nacido de muy Bajo Peso/crecimiento & desarrollo , Leche Humana , Aumento de Peso , Método Doble Ciego , Alimentos Fortificados/efectos adversos , Estudios ProspectivosRESUMEN
OBJECTIVE: To compare the weight and height gain and the frequency of clinical complications in preterm newborns weighing less than 1,500 g, exclusively fed human milk or fortified human milk until reaching 1,800 g. METHODS: Prospective double-blind randomized controlled trial involving 40 preterm infants weighing < 1,500 g at birth and Asunto(s)
Alimentos Fortificados
, Recien Nacido Prematuro/crecimiento & desarrollo
, Recién Nacido de muy Bajo Peso/crecimiento & desarrollo
, Leche Humana
, Aumento de Peso
, Método Doble Ciego
, Femenino
, Alimentos Fortificados/efectos adversos
, Humanos
, Recién Nacido
, Masculino
, Estudios Prospectivos
RESUMEN
Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC(50) of 0.42 microM (50% FBS) and a human whole blood IC(50) of 1.3 microM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100mg/kg.
Asunto(s)
Analgésicos no Narcóticos/síntesis química , Imidazoles/síntesis química , Imidazoles/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Fenantrenos/síntesis química , Fenantrenos/farmacología , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/farmacología , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Cobayas , Humanos , Hiperalgesia/inducido químicamente , Imidazoles/sangre , Imidazoles/química , Concentración 50 Inhibidora , Estructura Molecular , Fenantrenos/sangre , Fenantrenos/química , Prostaglandina-E Sintasas , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Receptores de Prostaglandina E/antagonistas & inhibidores , Tiofenos/síntesis química , Tiofenos/farmacocinética , Animales , Encéfalo/metabolismo , Línea Celular , Semivida , Humanos , Farmacocinética , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Tiofenos/farmacología , Distribución TisularRESUMEN
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.