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
- PMID: 33556572[PubMed].
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