Multiparameter optimization in CNS drug discovery: design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT2C) receptor agonists with exquisite functional selectivity over 5-HT2A and 5-HT2B receptors.
J Med Chem
; 57(12): 5258-69, 2014 Jun 26.
Article
em En
| MEDLINE
| ID: mdl-24878222
ABSTRACT
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Azepinas
/
Fármacos do Sistema Nervoso Central
/
Receptor 5-HT2A de Serotonina
/
Receptor 5-HT2B de Serotonina
/
Receptor 5-HT2C de Serotonina
/
Agonistas do Receptor 5-HT2 de Serotonina
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Reino Unido