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

  • Bioorg Med Chem Lett. 2016 Jul 1;26(13):3029-3033. doi: 10.1016/j.bmcl.2016.05.010.
Michael R Wood  1 ,  Meredith J Noetzel  2 ,  Julie L Engers  3 ,  Katrina A Bollinger  3 ,  Bruce J Melancon  2 ,  James C Tarr  3 ,  Changho Han  3 ,  Mary West  3 ,  Alison R Gregro  3 ,  Atin Lamsal  3 ,  Sichen Chang  3 ,  Sonia Ajmera  3 ,  Emery Smith  4 ,  Peter Chase  4 ,  Peter S Hodder  5 ,  Michael Bubser  3 ,  Carrie K Jones  6 ,  Corey R Hopkins  7 ,  Kyle A Emmitte  7 ,  Colleen M Niswender  6 ,  Michael W Wood  8 ,  Mark E Duggan  8 ,  P Jeffrey Conn  6 ,  Thomas M Bridges  9 ,  Craig W Lindsley  10
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 4. The Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL, USA.
  • 5. Amgen Inc., Thousand Oaks, CA, USA.
  • 6. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 7. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 8. Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
  • 9. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: [email protected].
  • 10. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 27185330 DOI: 10.1016/j.bmcl.2016.05.010
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 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.

Keywords
M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure–Activity Relationship (SAR).
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