RESUMO
Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.
Assuntos
Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/farmacocinética , Constipação Intestinal/tratamento farmacológico , Descoberta de Drogas , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Animais , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/uso terapêutico , Doença Crônica , Cobaias , Humanos , Estrutura Molecular , Ratos , Agonistas do Receptor 5-HT4 de Serotonina/química , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.
Assuntos
Compostos Heterocíclicos/química , Piperazinas/química , Agonistas do Receptor 5-HT4 de Serotonina/química , Administração Oral , Animais , Linhagem Celular , Descoberta de Drogas , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/farmacocinética , Humanos , Masculino , Estrutura Molecular , Especificidade de Órgãos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT4 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
5-HT(4) receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT(4) receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a "secondary" binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT(4) agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT(4) agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT(4) agonist for the potential treatment of gastrointestinal motility-related disorders.