Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.
AUTHORS
Reid
PRPaul R ,
Bridges
TM Thomas M ,
Sheffler
DJ Douglas J ,
Cho
HP Hyekyung P ,
Lewis
LM L Michelle ,
Days
E Emily ,
Daniels
JS J Scott ,
Jones
CK Carrie K ,
Niswender
CM Colleen M ,
Weaver
CD C David ,
Conn
PJ P Jeffrey ,
Lindsley
CW Craig W ,
Wood
MR Michael R .
Bioorganic & medicinal chemistry letters. 2011 5 1; 21(9).
2697-701
- PMID: 21194936[PubMed].
- PMCID: PMC3082000.
- NIHMSID: NIHMS262400
ABSTRACT
This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M(1) PAM with an in vitro profile comparable to the prototypical M(1) PAM, BQCA, but with an improved brain to plasma ratio.