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
The stereoselective acetylation of meso-2,2-dimethyl-1,3-cyclohexanediol by vinyl acetate in the presence of three lipases gave the (1R,3S)-monoester in high enantiomeric excess (ee > or = 98%). The hydrolysis of the corresponding meso-diacetate in the presence of Candida antarctica lipase in phosphate buffer provided the opposite enantiomer. Optically active monoacetates were converted to both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone, a versatile chiral building block.