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

• Published in: Bioorganic & medicinal chemistry letters Vol. 37; p. 127838
• Main Authors: Kent, Caitlin N., Fulton, Mark G., Stillwell, Kaylee J., Dickerson, Jonathan W., Loch, Matthew T., Rodriguez, Alice L., Blobaum, Anna L., Boutaud, Olivier, Rook, Jerri L., Niswender, Colleen M., Conn, P. Jeffrey, Lindsley, Craig W.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.04.2021
• Subjects: Metabotropic glutamate receptor; mGlu4; Positive allosteric modulator (PAM); Structure-activity-relationship (SAR); mGlu4; Structure-activity-relationship (SAR); Positive allosteric modulator (PAM); Metabotropic glutamate receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.127838

[Display omitted] 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.