Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1869-72. doi: 10.1016/j.bmcl.2016.03.031. Epub 2016 Mar 10.

Abstract

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.

Keywords: Metabotropic glutamate receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure–activity relationship (SAR); mGlu(1).

Publication types

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

MeSH terms

  • Allosteric Regulation / drug effects
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Coumarins / chemistry*
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Stability
  • Furans / chemistry*
  • Furans / pharmacology*
  • Humans
  • Isoindoles / blood
  • Isoindoles / chemistry*
  • Isoindoles / pharmacology*
  • Molecular Structure
  • Phthalimides / blood
  • Phthalimides / chemistry
  • Phthalimides / pharmacology
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Coumarins
  • Furans
  • Isoindol-1-one
  • Isoindoles
  • Phthalimides
  • Receptors, Metabotropic Glutamate
  • VU0486321
  • phthalimide