Discovery And Optimization Of A Novel Cns Penetrant Series Of Mglu(4) Pams Based On A 1,4-Thiazepane Core With In Vivo Efficacy In A Preclinical Parkinsonian Model

A high throughput screen (HTS) identified a novel, but weak (EC50 = 6.2 mu M, 97% Glu Max) mGlu(4) PAM che-motype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu(4) PAM VU6022296 (EC50 = 32.8 nM, 108% Glu Max) with good CNS penetration (K-p = 0.45, K-p,K-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.