RESUMO
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
Assuntos
Azepinas/síntese química , Pirimidinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Animais , Azepinas/química , Azepinas/farmacologia , Azepinas/uso terapêutico , Modelos Animais de Doenças , Cães , Masculino , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Incontinência Urinária/tratamento farmacológicoRESUMO
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Assuntos
Pirimidinonas/química , Pirimidinonas/uso terapêutico , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Pirimidinonas/farmacologia , Receptor 5-HT2B de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Uretra/efeitos dos fármacos , Incontinência Urinária/tratamento farmacológicoRESUMO
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
Assuntos
Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/síntese química , Desenho de Fármacos , Receptores de Dopamina D3/agonistas , Administração Intranasal , Animais , Cristalografia por Raios X , Cães , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Receptores de Dopamina D3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.