RESUMEN
The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.
Asunto(s)
Diseño de Fármacos , Glicósidos/farmacología , Fenitoína/análogos & derivados , Piridonas/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Triazoles/farmacología , Relación Dosis-Respuesta a Droga , Glicósidos/síntesis química , Glicósidos/química , Humanos , Estructura Molecular , Fenitoína/química , Fenitoína/farmacología , Piridonas/síntesis química , Piridonas/química , Transportador 2 de Sodio-Glucosa , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
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).
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Descubrimiento de Drogas , Receptores de Serotonina 5-HT3/efectos de los fármacos , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacologíaRESUMEN
An indazole based series of glucocorticoid receptor agonists is reported. The SAR exploration of this scaffold yielded compounds with nanomolar affinity for the glucocorticoid receptor with indications of selectivity for the preferred transrepression mechanism; in vivo efficacy was observed in the mouse LPS induced TNFalpha model for compound 28.
Asunto(s)
Antiinflamatorios/química , Indazoles/química , Receptores de Glucocorticoides/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Indazoles/síntesis química , Indazoles/farmacología , Ratones , Receptores de Glucocorticoides/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.