RESUMO
We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
Assuntos
Receptor 5-HT2B de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinética , Animais , Sítios de Ligação , Masculino , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptor 5-HT2B de Serotonina/química , Antagonistas da Serotonina/classificaçãoRESUMO
A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.