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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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).

Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Volume26
Issue number12
Pages (from-to)2915-2919
Number of pages5
ISSN0960-894X
DOIs
Publication statusPublished - 15 Jun 2016
Externally publishedYes

Bibliographical note

Copyright © 2016 Elsevier Ltd. All rights reserved.

    Research areas

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

ID: 213595613