Open AccessSpiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1H-benzimidazol-2-ones as mGlu2 Receptor PAMs
Author(s) -
Ana Isabel de Lucas,
Javier Martínez Vega,
Encarnación Matesanz,
María Lourdes Linares,
Aránzazu García Molina,
Gary Tresadern,
Hilde Lavreysen,
Andrés A. Trabanco,
José M. Cid
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00350
Subject(s) - oxindole , piperidine , metabotropic glutamate receptor 2 , chemistry , allosteric regulation , combinatorial chemistry , pharmacology , computational biology , stereochemistry , metabotropic glutamate receptor , receptor , biochemistry , biology , agonist , catalysis
Starting from two weak mGlu 2 receptor positive allosteric modulator (PAM) HTS hits ( 4 and 5 ), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1 H -benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR 2 PAMs.