Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu2) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores

J Med Chem. 2019 Jan 10;62(1):378-384. doi: 10.1021/acs.jmedchem.8b01266. Epub 2018 Oct 31.

Abstract

A scaffold hopping exercise from a monocyclic mGlu2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu2 NAM potency, selectivity (versus mGlu3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amides / chemistry*
  • Amides / metabolism
  • Amides / pharmacokinetics
  • Animals
  • Central Nervous System / metabolism*
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Pyrazoles / chemistry
  • Pyridines / chemistry
  • Pyrimidines / chemistry
  • Rats
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Protein Isoforms
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • pyrazolo(1,5-a)pyrimidine
  • thienopyridine