Discovery of a novel 3,4-dimethylcinnoline carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping

[Display omitted] •Novel 2.4-dimehtylcinnoline-based M4 PAMs.•Utility of scaffold hopping to improve properties/DMPK.•Balanced human and rat M4 PAM potency. This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high p...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2019-11, Vol.29 (21), p.126678-126678, Article 126678
Hauptverfasser:	Temple, Kayla J., Engers, Julie L., Long, Madeline F., Gregro, Alison R., Watson, Katherine J., Chang, Sichen, Jenkins, Matthew T., Luscombe, Vincent B., Rodriguez, Alice L., Niswender, Colleen M., Bridges, Thomas M., Conn, P. Jeffrey, Engers, Darren W., Lindsley, Craig W.
Format:	Artikel
Sprache:	eng
Schlagworte:	Muscarinic acetylcholine receptor Positive allosteric modulator (PAM) Structure activity relationship (SAR)
Online-Zugang:	Volltext
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Zusammenfassung:	[Display omitted] •Novel 2.4-dimehtylcinnoline-based M4 PAMs.•Utility of scaffold hopping to improve properties/DMPK.•Balanced human and rat M4 PAM potency. This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2019.126678