RESUMEN
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Asunto(s)
Benzazepinas/química , Antagonistas de los Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Animales , Benzazepinas/farmacocinética , Perros , Semivida , Haplorrinos , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Niacinamida/análogos & derivados , Niacinamida/química , Niacinamida/farmacocinética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.