RESUMEN
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 µM). Compound 6s demonstrated free-plasma exposures above the IC50 (â¼50×) with a brain-to-plasma ratio of â¼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
Asunto(s)
Cognición/efectos de los fármacos , Ciclopropanos/síntesis química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Piperazinas/síntesis química , Receptores Histamínicos H3/metabolismo , Compuestos de Espiro/síntesis química , Animales , Azetidinas/síntesis química , Azetidinas/farmacocinética , Azetidinas/farmacología , Células CHO , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Perros , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Antagonistas de los Receptores Histamínicos H3/farmacología , Humanos , Aprendizaje/efectos de los fármacos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/genética , Reconocimiento en Psicología/efectos de los fármacos , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; µ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; µ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.
Asunto(s)
Benzamidas/química , Receptores Opioides kappa/antagonistas & inhibidores , Tropanos/química , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Línea Celular Tumoral , Diuresis/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores Opioides kappa/metabolismo , Relación Estructura-Actividad , Tropanos/síntesis química , Tropanos/farmacocinéticaRESUMEN
Previously, potent factor Xa inhibitors were described based on the 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one bicyclic core and a 4-methoxyphenyl P1 moiety. This manuscript describes 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and related bicyclic cores with the 3-aminobenzisoxazole P1 moiety. Many of these compounds are potent, selective, and efficacious inhibitors of coagulation factor Xa.
Asunto(s)
Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Inhibidores de Serina Proteinasa/síntesis química , Anticoagulantes/farmacología , Humanos , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Especificidad por Sustrato , Tromboembolia/tratamiento farmacológicoRESUMEN
Previously, potent factor Xa inhibitors were described based on a pyrazole core. Modifications of the pyrazole core have provided additional novel, highly potent factor Xa inhibitors. This manuscript will describe the synthesis and biological activity of factor Xa inhibitors containing the 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and related bicyclic cores. Many of these compounds are potent, selective, and orally bioavailable inhibitors of coagulation factor Xa.