Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1 H-benzimidazol-2-ones as mGlu2 Receptor PAMs

Ana Isabel de Lucas; Juan Antonio Vega; Encarnación Matesanz; María Lourdes Linares; Aránzazu García Molina; Gary Tresadern; Hilde Lavreysen; Andrés A Trabanco; José María Cid

doi:10.1021/acsmedchemlett.9b00350

Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1 H-benzimidazol-2-ones as mGlu₂ Receptor PAMs

ACS Med Chem Lett. 2019 Oct 10;11(3):303-308. doi: 10.1021/acsmedchemlett.9b00350. eCollection 2020 Mar 12.

Authors

Ana Isabel de Lucas¹, Juan Antonio Vega¹, Encarnación Matesanz¹, María Lourdes Linares¹, Aránzazu García Molina¹, Gary Tresadern², Hilde Lavreysen³, Andrés A Trabanco¹, José María Cid¹

Affiliations

¹ Discovery Chemistry, Janssen Research & Development, Division of Janssen-Cilag S.A., Jarama 75A, Toledo 45007, Spain.
² Computational Chemistry, Discovery Neuroscience, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
³ Discovery Neuroscience, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.

Abstract

Starting from two weak mGlu₂ 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)-1H-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 mGluR₂ PAMs.