RESUMEN
AIMS: To assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥1500 mg/day) and pioglitazone (≥30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A1c [HbA1c] ≥7.5% and ≤11%). METHODS: This placebo-controlled, double-blind study included 313 patients, mean baseline HbA1c=8.7%, who were randomized to receive sitagliptin 100 mg/day or placebo for 26 weeks. RESULTS: The addition of sitagliptin led to significant (P<.001) mean changes from baseline relative to placebo in HbA1c (-0.7%), fasting plasma glucose (-1.0 mmol/L), and 2-h post-meal glucose (-2.2 mmol/L). In patients with baseline HbA1c ≥9.0%, mean changes from baseline in HbA1c were -1.6% and -0.8% for the sitagliptin and placebo groups, respectively (between-group difference -0.8%; P<.001). The incidences of reported adverse events were generally similar between the treatment groups. Incidences of symptomatic hypoglycemia were 7/157 [4.5%] and 6/156 [3.8%] in the sitagliptin and placebo groups, respectively (P=.786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance. CONCLUSIONS: In this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Pirazinas/uso terapéutico , Tiazolidinedionas/uso terapéutico , Triazoles/uso terapéutico , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/prevención & control , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Perdida de Seguimiento , Metformina/efectos adversos , Persona de Mediana Edad , PPAR gamma/agonistas , Pacientes Desistentes del Tratamiento , Pioglitazona , Pirazinas/efectos adversos , Fosfato de Sitagliptina , Tiazolidinedionas/efectos adversos , Triazoles/efectos adversos , Adulto JovenRESUMEN
A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Asunto(s)
Androstadienos/síntesis química , Androstadienos/farmacología , Receptor beta de Estrógeno/agonistas , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstadienos/química , Animales , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Receptores Androgénicos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/químicaRESUMEN
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Asunto(s)
Androstenodiol/análogos & derivados , Androstenodiol/farmacología , Receptor beta de Estrógeno/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodiol/síntesis química , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Oxatiinas/química , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Ligandos , RatasRESUMEN
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Asunto(s)
Oxatiinas/farmacología , Pirrolidinas/química , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Ligandos , Modelos Moleculares , Oxatiinas/química , Receptores de Estrógenos/metabolismoRESUMEN
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
Asunto(s)
Cromanos/química , Cromanos/farmacología , Receptor alfa de Estrógeno/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Sitios de Unión , Línea Celular , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Ligandos , Modelos Químicos , Estructura Molecular , Tamaño de los Órganos , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Útero/efectos de los fármacosRESUMEN
A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
Asunto(s)
Indenos/síntesis química , Indenos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Alquilación , Animales , Borohidruros , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Clorhidrato de Raloxifeno/farmacología , Ratas , Receptores de Estrógenos/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of G6-amino derivatives of a lipophilic vancomycin analogue was prepared. Antibacterial activity of the analogues was inversely proportional to the degree of substitution of the G6-nitrogen. The fully substituted (quaternary) analogues were essentially inactive against vanA phenotype VREF strains but retained substantial activity against other bacteria, a profile reminiscent of teicoplanin.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Compuestos de Amonio Cuaternario/síntesis química , Vancomicina/análogos & derivados , Antibacterianos/química , Resistencia a Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Ligandos , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Animales , Compuestos Bicíclicos con Puentes/farmacología , Femenino , Cinética , Modelos Moleculares , Conformación Molecular , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Útero/efectos de los fármacosRESUMEN
A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.