RESUMEN
A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT(2C) agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT(2C) agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT(2B). Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
Asunto(s)
Azepinas/química , Pirimidinas/química , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/química , Incontinencia Urinaria/tratamiento farmacológico , Animales , Azepinas/síntesis química , Azepinas/farmacología , Células CHO , Línea Celular , Cricetinae , Cricetulus , Perros , Descubrimiento de Drogas , Humanos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , TransfecciónRESUMEN
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.
Asunto(s)
Azepinas/química , Fármacos del Sistema Nervioso Central/química , Pirimidinas/química , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/química , Animales , Azepinas/síntesis química , Azepinas/farmacología , Barrera Hematoencefálica/metabolismo , Células CHO , Fármacos del Sistema Nervioso Central/síntesis química , Fármacos del Sistema Nervioso Central/farmacología , Cricetulus , Perros , Diseño de Fármacos , Humanos , Células de Riñón Canino Madin Darby , Permeabilidad , Pirimidinas/síntesis química , Pirimidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Relación Estructura-Actividad , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológicoRESUMEN
The title reagent engaged in the modified Julia olefination with aldehydes under mild reaction conditions (DBU, CH(2)Cl(2), rt or -78 degrees C) to yield alpha,beta-unsaturated esters; aryl aldehydes and aliphatic aldehydes possessing significant chain branching elements gave trans alkene products with high stereoselectivity (E : Z up to >98 : 2), while straight chain aliphatic aldehydes gave cis products preferentially (Z : E up to 92 : 8).