Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2915-2919. doi: 10.1016/j.bmcl.2016.04.041. Epub 2016 Apr 19.

Abstract

This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).

Keywords: Metabotropic glutamate receptor; Parkinson’s disease; Positive allosteric modulator (PAM); Structure–activity relationship (SAR); mGlu(4).

MeSH terms

  • Allosteric Regulation / drug effects
  • Amides / chemistry
  • Amides / metabolism
  • Amides / pharmacology*
  • Animals
  • Central Nervous System / drug effects*
  • Central Nervous System / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Picolines / chemistry
  • Picolines / metabolism
  • Picolines / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 3-aminopicolinamide
  • Amides
  • Picolines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 4