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

Authors

Kent CN Caitlin N , Fulton MG Mark G , Stillwell KJ Kaylee J , Dickerson JW Jonathan W , Loch MT Matthew T , Rodriguez AL Alice L , Blobaum AL Anna L , Boutaud O Olivier , Rook JL Jerri L , Niswender CM Colleen M , Jeffrey Conn P P , Lindsley CW Craig W .
Bioorganic & medicinal chemistry letters. 2021 2 5; ().
127838

Abstract

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

Tags: 2021