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

Michael R. Wood, Meredith J. Noetzel, Julie L. Engers, Katrina A. Bollinger, Bruce J. Melancon, James C. Tarr, Changho Han, Mary West, Alison R. Gregro, Atin Lamsal, Sichen Chang, Sonia Ajmera, Emery Smith, Peter Chase, Peter S. Hodder, Michael Bubser, Carrie K. Jones, Corey R. Hopkins, Kyle A. Emmitte, Colleen M. NiswenderMichael W. Wood, Mark E. Duggan, P. Jeffrey Conn, Thomas M. Bridges, Craig W. Lindsley

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 Kp = 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 Kp > 10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.

Original languageEnglish
Pages (from-to)3029-3033
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number13
StatePublished - 1 Jul 2016


  • M
  • Muscarinic acetylcholine receptor
  • Positive allosteric modulator (PAM)
  • Schizophrenia
  • Structure-Activity Relationship (SAR)


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