RESUMO
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.
Assuntos
Amidas/química , Amidas/farmacologia , Cicloexanos/química , Cicloexanos/farmacologia , Receptor de Glutamato Metabotrópico 5/química , Regulação Alostérica , Amidas/síntese química , Amidas/farmacocinética , Animais , Cicloexanos/síntese química , Cicloexanos/farmacocinética , Células HEK293 , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
