RESUMO
Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.
Assuntos
Azepinas/farmacologia , Descoberta de Drogas , Síndrome do Intestino Irritável/tratamento farmacológico , Receptores 5-HT3 de Serotonina/metabolismo , Administração Oral , Animais , Azepinas/administração & dosagem , Azepinas/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Serotonin type 3 (5-HT(3)) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold-Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.
Assuntos
Síndrome do Intestino Irritável/tratamento farmacológico , Receptores 5-HT3 de Serotonina/química , Agonistas do Receptor 5-HT3 de Serotonina/química , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Imidazóis/química , Indóis/química , Camundongos , Microssomos Hepáticos/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Agonistas do Receptor 5-HT3 de Serotonina/síntese química , Agonistas do Receptor 5-HT3 de Serotonina/uso terapêuticoRESUMO
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).
Assuntos
Benzoxazóis/química , Benzoxazóis/farmacologia , Descoberta de Drogas , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologiaRESUMO
A class of inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2) was discovered. These compounds have demonstrated activity against the enzyme with IC50 values as low as 130 nM and suppress the expression of TNFalpha in U937 cells. These represent the first small molecule inhibitors of MK-2 to be reported.