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
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.
Asunto(s)
Síndrome del Colon Irritable/tratamiento farmacológico , Receptores de Serotonina 5-HT3/química , Agonistas del Receptor de Serotonina 5-HT3/química , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Imidazoles/química , Indoles/química , Ratones , Microsomas Hepáticos/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Agonistas del Receptor de Serotonina 5-HT3/síntesis química , Agonistas del Receptor de Serotonina 5-HT3/uso terapéuticoRESUMEN
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
Amiloride (1), the prototypical epithelial sodium channel (ENaC) blocker, has been administered with limited success as aerosol therapy for improving pulmonary function in patients with the genetic disorder cystic fibrosis. This study was conducted to synthesize and identify more potent, less reversible ENaC blockers, targeted for aerosol therapy and possessing minimal systemic renal activity. A series of novel 2-substituted acylguanidine analogues of amiloride were synthesized and evaluated for potency and reversibility on bronchial ENaC. All compounds tested were more potent and less reversible at blocking sodium-dependent short-circuit current than amiloride. Compounds 30-34 showed the greatest potency on ENaC with IC(50) values below 10 nM. A regioselective difference in potency was found (compounds 30, 39, and 40), whereas no stereospecific (compounds 33, 34) difference in potency on ENaC was displayed. Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloride and displayed the lowest IC(50) value ever reported for an ENaC blocker.
Asunto(s)
Bronquitis Crónica/tratamiento farmacológico , Fibrosis Quística/tratamiento farmacológico , Guanidinas/síntesis química , Pirazinas/síntesis química , Bloqueadores de los Canales de Sodio/síntesis química , Canales de Sodio/efectos de los fármacos , Animales , Bronquios/efectos de los fármacos , Bronquios/fisiología , Técnicas Químicas Combinatorias , Perros , Canales Epiteliales de Sodio , Guanidinas/química , Guanidinas/farmacología , Modelos Moleculares , Pirazinas/química , Pirazinas/farmacología , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/fisiología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/fisiología , Estereoisomerismo , Relación Estructura-Actividad , Técnicas de Cultivo de TejidosRESUMEN
A simple and efficient method for removing excess acyl donors following enzymatic acylations in organic solvents was developed. This method is based on selective chemical scavenging of acyl donors using an amino-functionalized solid support, and does not affect the desired acylated product. A wide variety of different acyl donors, including vinyl and trifluoroethyl esters and vinyl carbonates, can be quantitatively removed by this method, thus providing a simple and highly efficient tool for purification of reaction products after enzymatic acylation.