RESUMO
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
The conversion of 2-butyn-1,4-diol to (Z)-2,4-diiodobut-2-en-1-ol proceeded efficiently using in situ generated trimethylsilyl iodide. Coupling with Grignard reagents and other nucleophiles delivered (2Z)-2-iodo allylic alcohols. The geometry of the products was established by nOe.
Assuntos
Butileno Glicóis/química , Propanóis/síntese química , Espectroscopia de Ressonância Magnética , Propanóis/química , Espectrofotometria InfravermelhoRESUMO
The first enantioselective synthesis of a chamigrane sesquiterpene, (+)-majusculone, has been completed. The quaternary center was generated asymmetrically by alkylidene carbene insertion, with retention of absolute configuration, from a diastereomerically pure ketal.