Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5, 6-dimethyl-4-(piperidin-1-yl)thieno[2, 3-d]pyrimidine core. Issue 13 (1st July 2016)

• Record Type: Journal Article
• Authors: Wood, Michael R.; Noetzel, Meredith J.; Engers, Julie L.; Bollinger, Katrina A.; Melancon, Bruce J.; Tarr, James C.; Han, Changho; West, Mary; Gregro, Alison R.; Lamsal, Atin; Chang, Sichen; Ajmera, Sonia; Smith, Emery; Chase, Peter; Hodder, Peter S.; Bubser, Michael; Jones, Carrie K.; Hopkins, Corey R.; Emmitte, Kyle A.; Niswender, Colleen M.; Wood, Michael W.; Duggan, Mark E.; Conn, P. Jeffrey; Bridges, Thomas M.; Lindsley, Craig W.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 13(2016)
• Page Start: 3029
• Page End: 3033
• Publication Date: 2016-07-01
• Subjects: M4 -- Muscarinic acetylcholine receptor -- Positive allosteric modulator (PAM) -- Schizophrenia -- Structure–Activity Relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.05.010
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5, 6-dimethyl-4-(piperidin-1-yl)thieno[2, 3- d ]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma K p = 0.74), within the original core after several rounds of optimization; however, the thieno[2, 3- d ]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K p > 10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.