From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-β-carbolines: A new class of orally bioavailable mGluR1 antagonists

Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic β-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.

Graphical abstractA new class of orally available mGluR1 antagonists was identified by replacement of the known pyrrole core with a β-carboline template suitably substituted at the position C-6.Figure optionsDownload full-size imageDownload as PowerPoint slide