RESUMEN
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Quinolonas/química , Quinolonas/farmacología , Sitio Alostérico/efectos de los fármacos , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Isocitrato Deshidrogenasa/química , Isocitrato Deshidrogenasa/genética , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Mutación Puntual , Quinolonas/farmacocinéticaRESUMEN
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
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.
Asunto(s)
Resistencia a la Insulina , PPAR delta/agonistas , Transferencia Resonante de Energía de Fluorescencia , Relación Estructura-ActividadRESUMEN
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.