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
en 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
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
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Azepinas
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Fármacos del Sistema Nervioso Central
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Receptor de Serotonina 5-HT2A
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Receptor de Serotonina 5-HT2B
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Receptor de Serotonina 5-HT2C
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Agonistas del Receptor de Serotonina 5-HT2
Límite:
Animals
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Humans
Idioma:
En
Año:
2014
Tipo del documento:
Article