RESUMO
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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Indazóis/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Compostos de Espiro/farmacologia , Animais , Sítios de Ligação , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/síntese química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/toxicidade , Cães , Desenho de Fármacos , Humanos , Indazóis/síntese química , Indazóis/metabolismo , Indazóis/toxicidade , Macaca fascicularis , Transtornos de Enxaqueca/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/metabolismo , Compostos de Espiro/toxicidade , Relação Estrutura-AtividadeRESUMO
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.