SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M PAMs
AUTHORS
Chopko
TCTrevor C ,
Han
CChangho ,
Gregro
ARAlison R ,
Engers
DWDarren W ,
Felts
ASAndrew S ,
Poslusney
MSMike S ,
Bollinger
KAKatrina A ,
Morrison
RDRyan D ,
Bubser
MMichael ,
Lamsal
AAtin ,
Luscombe
VBVincent B ,
Cho
HPHyekyung P ,
Schnetz-Boutaud
NCNathalie C ,
Rodriguez
ALAlice L ,
Chang
SSichen ,
Daniels
JSJ Scott ,
Stec
DFDonald F ,
Niswender
CMColleen M ,
Jones
CKCarrie K ,
Wood
MRMichael R ,
Wood
MWMichael W ,
Duggan
MEMark E ,
Brandon
NJNicholas J ,
Conn
PJP Jeffrey ,
Bridges
TMThomas M ,
Lindsley
CWCraig W ,
Melancon
BJBruce J .
Bioorganic & medicinal chemistry letters. 2019 6 20; 29(16).
2224-2228
- PMID: 31248774[PubMed].
ABSTRACT
This letter describes progress towards an M PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Tags: 2019