RESUMEN
An HTS campaign led to the identification of 4-pyrroldino-2-(pyridin-2-yl)pyrimidine compound 1 as an RANKL-induced osteoclastogenesis inhibitor. The compound 1 showed high clearance values in microsomes, however. Modification of the pyrrolidino group to a benzylamino group improved human microsomal stability with a slight loss of in vitro activity. Substitution at the ortho position of the benzyl group ameliorated in vitro activity, and further fluorination of the benzyl group improved microsomal stability in rodents. Representative members of this series, compounds 20 and 23, exhibited efficacy in RANKL-induced osteopenic mice when administered orally at 0.3 mg/kg.
Asunto(s)
Resorción Ósea/tratamiento farmacológico , Osteoclastos/efectos de los fármacos , Pirimidinas/química , Pirimidinas/uso terapéutico , Ligando RANK/metabolismo , Administración Oral , Animales , Resorción Ósea/metabolismo , Línea Celular , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Isoquinolinas/química , Isoquinolinas/síntesis química , Triazoles/química , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Línea Celular , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Isoquinolinas/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as glycine transporter 1 (GlyT1) inhibitors. Structure-activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Triazoles/síntesis química , Animales , Maleato de Dizocilpina/farmacología , Femenino , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Wistar , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.