RESUMEN
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Adenosina Trifosfato/metabolismo , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/administración & dosificación , Humanos , Enlace de Hidrógeno , Isoenzimas/antagonistas & inhibidores , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Ftalimidas/química , Relación Estructura-ActividadRESUMEN
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Quinazolinonas/síntesis química , Receptores de Ghrelina/antagonistas & inhibidores , Administración Oral , Animales , Unión Competitiva , Glucemia/análisis , Línea Celular , Ingestión de Alimentos/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Quinazolinonas/química , Quinazolinonas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Pérdida de Peso/efectos de los fármacosRESUMEN
Medicinal chemistry, as a field, has moved into new and unwelcome territory. How did we get here, and what might be the way out?
Asunto(s)
Descubrimiento de Drogas , Química Farmacéutica , Técnicas Químicas Combinatorias , Hepacivirus/enzimología , Biblioteca de Péptidos , Inhibidores de Proteasas/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Asunto(s)
Acetatos/farmacología , Oxazoles/química , PPAR alfa/agonistas , PPAR gamma/agonistas , Acetatos/administración & dosificación , Acetatos/síntesis química , Administración Oral , Animales , Glucemia/efectos de los fármacos , HDL-Colesterol/sangre , HDL-Colesterol/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ligandos , Ratones , Ratones Mutantes , Ratones Obesos , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Relación Estructura-Actividad , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pirrolidinonas/química , Pirrolidinonas/farmacología , Tiofenos/química , Tiofenos/farmacología , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Línea Celular , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Macaca fascicularis , Pirrolidinonas/síntesis química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/síntesis químicaRESUMEN
Elevation of plasma free fatty acids has been linked with insulin resistance and diabetes. Inhibition of lipolysis may provide a mechanism to decrease plasma fatty acids, thereby improving insulin sensitivity. Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores, and its inhibition may thus improve insulin sensitivity and blood glucose handling in type 2 diabetes. In rat adipocytes, forskolin-activated lipolysis was blocked by in vitro addition of a potent and selective HSL inhibitor or by prior treatment of the animals themselves. Antilipolytic effects also were demonstrated in overnight-fasted mice, rats, and dogs with species-dependent effects on plasma free fatty acid levels but with similar reductions in plasma glycerol being observed in all species. Inhibition of HSL also reduced hyperglycemia in streptozotocin-induced diabetic rats. The data support a connection between adipose tissue lipolysis and plasma glucose levels.
Asunto(s)
Glucemia/metabolismo , Lípidos/sangre , Esterol Esterasa/antagonistas & inhibidores , Células 3T3-L1 , Adipocitos/metabolismo , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Perros , Ayuno , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Glicerol/análisis , Glicerol/metabolismo , Humanos , Insulina/análisis , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Lipólisis , Masculino , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Especificidad de la Especie , Esterol Esterasa/genética , Factores de TiempoRESUMEN
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.