Discovery and optimization of a novel CNS penetrant series of mGlu4 PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model.

Abstract

A high throughput screen (HTS) identified a novel, but weak (EC50 = 6.2 μM, 97% Glu Max) mGlu4 PAM chemotype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu4 PAM VU6022296 (EC50 = 32.8 nM, 108% Glu Max) with good CNS penetration (Kp = 0.45, Kp,uu = 0.70) and enantiopreference. Finally, VU6022296 displayed robust, dose-dependent efficacy in reversing Haloperidol-Induced Catalepsy (HIC), a rodent preclinical Parkinson's disease model.

• Authors: Caitlin N Kent, Mark G Fulton, Kaylee J Stillwell, Jonathan W Dickerson, Matthew T Loch, Alice L Rodriguez, Anna L Blobaum, Olivier Boutaud, Jerri L Rook, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 37 Pg. 127838 (04 01 2021) ISSN: 1464-3405 [Electronic] England
• PMID: 33556572 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Neuroprotective Agents
• Receptors, Metabotropic Glutamate
• Haloperidol

Topics

• Allosteric Regulation (drug effects)
• Animals
• Catalepsy (chemically induced, drug therapy)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Discovery
• Haloperidol
• Mice
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Parkinson Disease (drug therapy)
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship