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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 CNCaitlin N , Fulton MGMark G , Stillwell KJKaylee J , Dickerson JWJonathan W , Loch MTMatthew T , Rodriguez ALAlice L , Blobaum ALAnna L , Boutaud OOlivier , Rook JLJerri L , Niswender CMColleen M , Jeffrey Conn PP , Lindsley CWCraig 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.



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