RESUMEN
A series of novel spirocyclic DGAT1 inhibitors containing the oxadiazole motif were designed and synthesized for biological evaluation. Several compounds exhibited potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activity. Optimization of the series led to the identification of five lead compounds 8, 9, 10, 11 and 12 that showed excellent in-vitro activity with IC50 values ranging from 7 to 20 nM against human DGAT1. All compounds demonstrated good druggability as well as microsomal stability and safety profiles such as hERG and CYP. Compound 12 significantly reduced plasma triglyceride levels in-vivo in the mouse model of acute lipid challenge. Significant reduction in plasma TG excursion was observed, thus indicating DGAT1 inhibition in-vivo.
Asunto(s)
Ácidos Carboxílicos , Diacilglicerol O-Acetiltransferasa , Inhibidores Enzimáticos , Animales , Ácidos Carboxílicos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Ratones , Oxadiazoles/farmacología , TriglicéridosRESUMEN
Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/química , Antagonistas del Receptor de Adenosina A1/farmacología , Hipoxantinas/química , Hipoxantinas/farmacología , Antagonistas del Receptor de Adenosina A1/síntesis química , Antagonistas del Receptor de Adenosina A1/farmacocinética , Animales , Espectroscopía de Resonancia Magnética con Carbono-13 , Cromatografía Liquida , Diseño de Fármacos , Células HEK293 , Humanos , Hipoxantinas/síntesis química , Hipoxantinas/farmacocinética , Masculino , Espectrometría de Masas , Espectroscopía de Protones por Resonancia Magnética , Ensayo de Unión Radioligante , Ratas , Ratas WistarRESUMEN
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
Asunto(s)
Oxidorreductasas de Alcohol/antagonistas & inhibidores , Ácidos Carboxílicos/química , Inhibidores Enzimáticos/química , Pirazoles/química , Tiofenos/química , Oxidorreductasas de Alcohol/metabolismo , Animales , Sitios de Unión , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacocinética , Simulación por Computador , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Riñón/enzimología , Riñón/metabolismo , Hígado/enzimología , Hígado/metabolismo , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/uso terapéutico , Ratas , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/uso terapéuticoRESUMEN
l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.
RESUMEN
Three new triterpenoids, designated as acinospesigenin-A (1), -B (2), and -C (3), isolated from the berries of Phytolacca acinosa, have been characterized as 3 beta-acetoxy-11 alpha,23-dihydroxytaraxer-14-en-28-oic acid, olean-12-en-23-al-2 beta,3 beta-dihydroxy-30-methoxycarbonyl-28-oic acid and olean-12-en-23-al-2 beta,3 beta,11 alpha-trihydroxy-30-methoxycarbonyl-28-oic acid, respectively. The compounds have shown antiedemic activity (LD(50) 10-15 mg/kg mass) in albino rats.
Asunto(s)
Phytolacca/química , Plantas Medicinales/química , Triterpenos/aislamiento & purificación , Animales , Edema/tratamiento farmacológico , Frutas/química , Miembro Posterior/efectos de los fármacos , India , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Hojas de la Planta/química , Ratas , Estereoisomerismo , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Four new alkaloids, characterized as 6-(2-hydroxyethyl)-5,6-dihydrosanguinarine (1), 6-acetonyl-5,6-dihydrosanguinarine (2), N-methyl-2,3,7,8-tetramethoxy-5,6-dihydrobenzophenanthridine-6-ethanoic acid (3), N-methyl-2,3,7,8-tetramethoxy-6-oxo-5,6-dihydrobenzophenanthridine (4), together with oxosanguinarine (5), spallidamine (6), 6-acetonyl-5,6-dihydrochelerythrine (7), 6-oxochelerythrine (8) and sanguidimerine (9) were isolated from the roots of Corydalis flabellata.
