Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2

  • Bioorg Med Chem Lett. 2021 Dec 1:53:128416. doi: 10.1016/j.bmcl.2021.128416.
Madeline F Long  1 ,  Rory A Capstick  1 ,  Paul K Spearing  1 ,  Julie L Engers  1 ,  Alison R Gregro  1 ,  Sean R Bollinger  1 ,  Sichen Chang  1 ,  Vincent B Luscombe  1 ,  Alice L Rodriguez  1 ,  Hyekyung P Cho  1 ,  Colleen M Niswender  2 ,  Thomas M Bridges  1 ,  P Jeffrey Conn  2 ,  Craig W Lindsley  3 ,  Darren W Engers  1 ,  Kayla J Temple  4
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 2. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, 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; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 34710625 DOI: 10.1016/j.bmcl.2021.128416
Abstract

This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.

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