RESUMEN
A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Fémur/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Pirimidinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Esterasas/metabolismo , Fémur/anatomía & histología , Fémur/crecimiento & desarrollo , Humanos , Ratones , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Asunto(s)
Benzopiranos/química , Inhibidores Enzimáticos/química , Esterasas/antagonistas & inhibidores , Animales , Benzopiranos/farmacocinética , Benzopiranos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Esterasas/metabolismo , Fémur/fisiología , Semivida , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/fisiopatología , Unión Proteica , Relación Estructura-ActividadRESUMEN
The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum -/- mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.
RESUMEN
The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Hipoglucemiantes/farmacología , Fenilbutiratos/farmacología , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Tioglicósidos/farmacología , Animales , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/química , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Absorción Intestinal/efectos de los fármacos , Masculino , Ratones Noqueados , Fenilbutiratos/administración & dosificación , Fenilbutiratos/síntesis química , Fenilbutiratos/química , Relación Estructura-Actividad , Tioglicósidos/administración & dosificación , Tioglicósidos/síntesis química , Tioglicósidos/químicaRESUMEN
The stability and activity of recombinant growth factors administered locally for the repair of damaged tissue can be directly influenced by the physical structure and chemical composition of the delivery matrix. This study describes a novel basic fibroblast growth factor-2 (FGF-2) delivery system synthesized by the conjugation of a structure-stabilizing polymer, hyaluronate (HA), with a sulfated glycosaminoglycan, heparin (HP), that has inherent specific binding sites for members of the FGF family. The biopolymers were formed via stable amine or labile imine bonds by coupling amine-modified HA with oxidized heparin. The addition of recombinant human FGF-2 resulted in the rapid binding of FGF-2 to the heparin segment of the hyaluronate-heparin (HAHP) conjugate. The FGF-2 was released in vitro from the imine-bonded (HAHPi) gels in the form of FGF-2-heparin complexes through the hydrolysis of the imine bonds. In contrast, the release of growth factor from the more stable amine-bonded (HAHPa) gels required treatment with free heparin or enzymatic digestion of the hyaluronate segment. Functional analysis of the released FGF-2 showed that the HAHP conjugate gels increased both the stability and activity of the growth factor.