Discovery of structurally distinct tricyclic M positive allosteric modulator (PAM) chemotypes
AUTHORS
Temple
KJKayla J ,
Long
MFMadeline F ,
Engers
JLJulie L ,
Watson
KJKatherine J ,
Chang
SSichen ,
Luscombe
VBVincent B ,
Rodriguez
ALAlice L ,
Niswender
CMColleen M ,
Bridges
TMThomas M ,
Conn
PJP Jeffrey ,
Engers
DWDarren W ,
Lindsley
CWCraig W .
Bioorganic & medicinal chemistry letters. 2019 11 11; 30(4).
126811
- PMID: 31787491[PubMed].
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