title: Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.
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.
authors.affiliation: Vanderbilt Institute of Chemical Biology/Chemical Synthesis Core, Nashville, TN 37232, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reid
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: L Michelle
authors.initials: LM
authors.lastname: Lewis
authors.forename: Emily
authors.initials: E
authors.lastname: Days
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
mesh_terms: D000494:Allosteric Regulation; D001921:Brain / Q000187:drug effects*; D002478:Cells, Cultured; D055808:Drug Discovery; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007211:Indoles; D015335:Molecular Probes; D043643:Receptor, Muscarinic M1; D013450:Sulfones; C560209:VU 0405652