Discovery of a novel 3, 4-dimethylcinnoline carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping. Issue 21 (1st November 2019)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 21(2019)
• Publication Date: 2019-11-01
• Subjects: M4 -- Muscarinic acetylcholine receptor -- Positive allosteric modulator (PAM) -- Structure activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126678
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Novel 2.4-dimehtylcinnoline-based M4 PAMs. Utility of scaffold hopping to improve properties/DMPK. Balanced human and rat M4 PAM potency. Abstract: 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.