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 journal › Journal article › Research › peer-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).
|Journal||Bioorganic & Medicinal Chemistry Letters|
|Number of pages||5|
|Publication status||Published - 15 Jun 2016|
Copyright © 2016 Elsevier Ltd. All rights reserved.
- 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