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.

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. Bioorg Med Chem Lett. 2021 Feb 05;:127838 Authors: Kent CN, Fulton MG, Stillwell KJ, Dickerson JW, Loch MT, Rodriguez AL, Blobaum AL, Boutaud O, Rook JL, Niswender CM, Jeffrey Conn P, Lindsley CW 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. PMID: 33556572 [PubMed - as supplied by publisher]
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research