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

Article abstract of DOI:10.1016/j.bmcl.2021.127838

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 (K_p = 0.45, K_p,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.