Discovery of structurally distinct tricyclic M positive allosteric modulator (PAM) chemotypes
Authors
Temple
KJ
Kayla J
,
Long
MF
Madeline F
,
Engers
JL
Julie L
,
Watson
KJ
Katherine J
,
Chang
S
Sichen
,
Luscombe
VB
Vincent B
,
Rodriguez
AL
Alice L
,
Niswender
CM
Colleen M
,
Bridges
TM
Thomas M
,
Conn
PJ
P Jeffrey
,
Engers
DW
Darren W
,
Lindsley
CW
Craig W
.
Bioorganic & medicinal chemistry letters. 2019 11 11; 30(4).
126811
Bioorganic & medicinal chemistry letters. 2019 11 11; 30(4).
126811
Abstract
This Letter details our efforts to develop new M PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M.
Tags: 2019