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

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).

• Authors: Rocco D Gogliotti, Darren W Engers, Pedro M Garcia-Barrantes, Joseph D Panarese, Patrick R Gentry, Anna L Blobaum, Ryan D Morrison, J Scott Daniels, Analisa D Thompson, Carrie K Jones, P Jeffrey Conn, Colleen M Niswender, Craig W Lindsley, Corey R Hopkins
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 12 Pg. 2915-2919 (06 15 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 27131990 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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