Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover

  • Bioorg Med Chem Lett. 2012 Oct 15;22(20):6481-5. doi: 10.1016/j.bmcl.2012.08.043.
Jason T Manka  1 ,  Paige N Vinson ,  Karen J Gregory ,  Ya Zhou ,  Richard Williams ,  Kiran Gogi ,  Emily Days ,  Satya Jadhav ,  Elizabeth J Herman ,  Hilde Lavreysen ,  Claire Mackie ,  José M Bartolomé ,  Gregor J Macdonald ,  Thomas Steckler ,  J Scott Daniels ,  C David Weaver ,  Colleen M Niswender ,  Carrie K Jones ,  P Jeffrey Conn ,  Craig W Lindsley ,  Shaun R Stauffer
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
PMID: 22981332 DOI: 10.1016/j.bmcl.2012.08.043
Abstract

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.

Products