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.
Rocco D Gogliotti  1 ,  Darren W Engers  2 ,  Pedro M Garcia-Barrantes  1 ,  Joseph D Panarese  1 ,  Patrick R Gentry  1 ,  Anna L Blobaum  2 ,  Ryan D Morrison  1 ,  J Scott Daniels  2 ,  Analisa D Thompson  1 ,  Carrie K Jones  3 ,  P Jeffrey Conn  3 ,  Colleen M Niswender  3 ,  Craig W Lindsley  4 ,  Corey R Hopkins  5
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
  • 5. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 27131990 DOI: 10.1016/j.bmcl.2016.04.041
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).