SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M PAMs
Authors
Chopko
TC
Trevor C
,
Han
C
Changho
,
Gregro
AR
Alison R
,
Engers
DW
Darren W
,
Felts
AS
Andrew S
,
Poslusney
MS
Mike S
,
Bollinger
KA
Katrina A
,
Morrison
RD
Ryan D
,
Bubser
M
Michael
,
Lamsal
A
Atin
,
Luscombe
VB
Vincent B
,
Cho
HP
Hyekyung P
,
Schnetz-Boutaud
NC
Nathalie C
,
Rodriguez
AL
Alice L
,
Chang
S
Sichen
,
Daniels
JS
J Scott
,
Stec
DF
Donald F
,
Niswender
CM
Colleen M
,
Jones
CK
Carrie K
,
Wood
MR
Michael R
,
Wood
MW
Michael W
,
Duggan
ME
Mark E
,
Brandon
NJ
Nicholas J
,
Conn
PJ
P Jeffrey
,
Bridges
TM
Thomas M
,
Lindsley
CW
Craig W
,
Melancon
BJ
Bruce J
.
Bioorganic & medicinal chemistry letters. 2019 6 20; 29(16).
2224-2228
Bioorganic & medicinal chemistry letters. 2019 6 20; 29(16).
2224-2228
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