RESUMEN
A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.
Asunto(s)
Amidas/química , Amidas/farmacología , Ciclohexanos/química , Ciclohexanos/farmacología , Receptor del Glutamato Metabotropico 5/química , Regulación Alostérica , Amidas/síntesis química , Amidas/farmacocinética , Animales , Ciclohexanos/síntesis química , Ciclohexanos/farmacocinética , Células HEK293 , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-ActividadRESUMEN
Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon.
