RESUMEN
Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Indazoles/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Compuestos de Espiro/farmacología , Animales , Sitios de Unión , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/síntesis química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/toxicidad , Perros , Diseño de Fármacos , Humanos , Indazoles/síntesis química , Indazoles/metabolismo , Indazoles/toxicidad , Macaca fascicularis , Trastornos Migrañosos/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Estructura Molecular , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/metabolismo , Compuestos de Espiro/toxicidad , Relación Estructura-ActividadRESUMEN
The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.