RESUMEN
The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Fenilalanina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Masculino , Péptidos/química , Fenilalanina/síntesis química , Fenilalanina/química , Fenilalanina/farmacocinética , Unión Proteica , Ratas , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas , Descubrimiento de Drogas , Amidas/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Células Cultivadas , Ciclización , Humanos , Hígado/metabolismo , Estructura Molecular , Unión Proteica/efectos de los fármacosRESUMEN
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.