RESUMEN
Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-ß in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Glucógeno Sintasa Quinasa 3/metabolismo , Semivida , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridinas/metabolismo , Piridinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasas/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Pirimidinas/farmacología , Animales , Células CHO , Cromatografía Líquida de Alta Presión , Cricetulus , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Humanos , Hipoglucemiantes/metabolismo , Espectrometría de Masas , Espectroscopía de Protones por Resonancia Magnética , Pirimidinas/química , Pirimidinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
AIM: Carotid endarterectomy (CEA) has been established as an effective treatment of carotid artery disease. Controversial remains the performance of CEA in elderly patients. Aim of this study is to report the mid-term (30 days) neurological outcome in patients older than 75 years after CEA with or without simultaneous aortocoronary bypass (CABG). METHODS: 599 patients undergoing CEA from January 2000 to December 2007 were enrolled. Isolated CEA was performed in 398/599 (66%) patients (group A). In 201/599(34%) patients (group B) was performed a combined procedure (CEA/CABG). 90/398(23%) patients of group A (group A1) and 49/201(24%) patients of group B (group B1) were >75 years old. 308/398 (77%) patients of group A (group A2) and 152/201 (76%) patients of group B (group B2) were <75 years old. Mortality, TIA and stroke rates as well as pre- and postoperative Rankin scale (RS) were reported. RESULTS: In isolated CEAs, mortality was higher in group A1 (A1:1.1% vs A2:0%, P=0.51). We found no significant differences in rates of TIA (A1:4.4% versus A2:3.2%, P=0.79) or stroke (A1:2.2% versus A2:1.9%, P=0.98). In CEA/CABG, mortality was 0% in group B1 and 5.9% in group B2 (P=0.17). No significant differences in rates of TIA (B1:2% versus B2:3%, P=0.76) or stroke (B1:2% versus B2:5%, P=0.70) were reported. Preoperative RS was the only positive predictor for postoperative stroke in groups A1 (P=0.02) and B1 (P=0.001). CONCLUSION: CEA is an appropriate and safe procedure in elderly patients. Under consideration should be the performance of CEA in elderly patients with high preoperative RS.
Asunto(s)
Enfermedades de las Arterias Carótidas/cirugía , Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria/cirugía , Endarterectomía Carotidea , Factores de Edad , Anciano , Anciano de 80 o más Años , Puente Cardiopulmonar , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/mortalidad , Distribución de Chi-Cuadrado , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Endarterectomía Carotidea/efectos adversos , Endarterectomía Carotidea/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Ataque Isquémico Transitorio/etiología , Masculino , Persona de Mediana Edad , Selección de Paciente , Análisis de Regresión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/etiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
The cytotoxic macrolide kendomycin was identified as a ligand of Bcl-xl, an anti-apoptotic member of the Bcl-2 protein family. Hydrolysis-stable and protonable semi-synthetic analogues have been obtained that retain cytotoxicity and Bcl-xl binding.
Asunto(s)
Apoptosis/efectos de los fármacos , Rifabutina/análogos & derivados , Proteína bcl-X/química , Línea Celular Tumoral , Humanos , Rifabutina/química , Rifabutina/farmacologíaRESUMEN
The identification of a highly efficacious anti-obesity agent remains an illusive goal. While many avenues of investigation have been pursued, none of the existing compounds claim much more than a 10% reduction in weight in humans (over a one year period with diet and exercise). Nonetheless, the potential reward for fulfilling this unmet medical need has kept interest levels high in the research community. The recent explosion of genetic information has identified numerous potential targets for drug screening. The melanocortin-4 receptor is a promising target and is currently being intensively investigated by many companies and academic research groups.
Asunto(s)
Peso Corporal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Receptor de Melanocortina Tipo 4/agonistas , Amidas/química , Amidas/farmacología , Amidas/uso terapéutico , Animales , Humanos , Estructura Molecular , Obesidad/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Piperazinas/química , Piperazinas/farmacología , Piperazinas/uso terapéutico , Relación Estructura-Actividad , SuccinatosRESUMEN
In the past decade there has been a significant growth in the sales of pharmaceutical drugs worldwide, but more importantly there has been a dramatic growth in the sales of single enantiomer drugs. The pharmaceutical industry has a rising demand for chiral intermediates and research reagents because of the continuing imperative to improve drug efficacy. This in turn impacts on researchers involved in preclinical discovery work. Besides traditional chiral pool and resolution of racemates as sources of chiral building blocks, many new synthetic methods including a great variety of catalytic reactions have been developed which facilitate the production of complex chiral drug candidates for clinical trials. The most ambitious technique is to synthesise homochiral compounds from non-chiral starting materials using chiral metal catalysts and related chemistry. Examples of the synthesis of chiral building blocks from achiral materials utilizing asymmetric hydrogenation and asymmetric epoxidation are presented.
Asunto(s)
Química Farmacéutica/métodos , Diseño de Fármacos , Catálisis , Compuestos Epoxi/química , Hidrogenación , Estructura Molecular , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , EstereoisomerismoRESUMEN
The synthesis of (2S)-2-benzyloxymethyl-3-(2-fluoro-4-methoxyphenyl)- propionic acid, (2S)-2-benzyloxymethyl-3-(2-fluoro-4-methylphenyl)propionic acid and (2S)-2-benzyl-oxymethyl-3-(2,4-dimethylphenyl)propionic acid has been achieved by TiCl4 mediated alkylation of the corresponding (4R)-4-benzyl-3-[3-(2-fluoro-4-methoxyphenyl-, 2-fluoro-4-methylphenyl-, 2,4- dimethylphenyl-)propionyl]-2-oxazolidinones, followed by hydrolysis of the chiral auxiliary. The stereochemistry of the alkylation reaction was confirmed by an X-ray crystal structure of (4R)-4-benzyl-3-[(2S)-2-benzyloxymethyl-3-(2- fluoro-4-methylphenyl)propionyl]-2-oxazolidinone.