RESUMEN
A new aluminosilicate zeolite, denoted EMM-28, has been successfully synthesized on a large scale using 1,1-(3,3-(1,3-phenylene)bis(propane-3,1-diyl))bis(1-methylpyrrolidinium) hydroxide as an organic structure directing agent (OSDA), which was scaled up to an â¼20 g scale with a yield of 77%. It crystallizes as thin plates (40-100 nm in thickness), and the corresponding powder X-ray diffraction (PXRD) pattern shows significant peak broadening which makes it insufficient for structure determination. Continuous rotation electron diffraction (cRED) data collected from 13 crystals were successfully used to solve and refine the structure of EMM-28. This illustrates that cRED data are capable of performing structure determination despite limited PXRD data quality. EMM-28 has a unique framework structure containing supercavities, >21 Å in size, connected by one-dimensional 10-ring channels. High-resolution transmission electron microscopy (HRTEM) confirmed the structure model. The structure of EMM-28 is related to several known zeolite structures with large cavities.
RESUMEN
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 first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.
RESUMEN
The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.
RESUMEN
The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Xilosa/análogos & derivados , Xilosa/farmacología , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/orina , Descubrimiento de Drogas , Glucosa/metabolismo , Humanos , Ratones , Especificidad por Sustrato , Xilosa/administración & dosificación , Xilosa/uso terapéuticoRESUMEN
The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.
Asunto(s)
Antihipertensivos/síntesis química , Quinasas Lim/antagonistas & inhibidores , Hipertensión Ocular/tratamiento farmacológico , Pirimidinas/síntesis química , Pirroles/síntesis química , Administración Tópica , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Glaucoma/tratamiento farmacológico , Glaucoma/fisiopatología , Guanidinas/síntesis química , Guanidinas/química , Guanidinas/farmacología , Técnicas In Vitro , Presión Intraocular/efectos de los fármacos , Ratones , Nitrilos/síntesis química , Nitrilos/química , Nitrilos/farmacología , Hipertensión Ocular/inducido químicamente , Hipertensión Ocular/fisiopatología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Porcinos , Urea/análogos & derivados , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
Chondroitin sulfate glycosaminoglycans are sulfated polysaccharides involved in cell division, neuronal development, and spinal cord injury. Here, we report the synthesis and identification of a chondroitin sulfate tetrasaccharide that stimulates the growth and differentiation of neurons. These studies represent the first, direct investigations into the structure-activity relationships of chondroitin sulfate using homogeneous synthetic molecules and define a tetrasaccharide as a minimal motif required for activity.
Asunto(s)
Sulfatos de Condroitina/farmacología , Neuronas/efectos de los fármacos , Animales , Células Cultivadas , Sulfatos de Condroitina/síntesis química , Sulfatos de Condroitina/química , Hipocampo , Microscopía Fluorescente , Neuronas/fisiología , Oligosacáridos/síntesis química , Oligosacáridos/metabolismoRESUMEN
A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9-11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12-14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB(1) receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K(i)=17-23nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12-14 have little affinity for the CB(1) receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17-19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have K(i)=26+/-4nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB(1) receptor.