Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping

  • Bioorg Med Chem Lett. 2017 Nov 15;27(22):4999-5001. doi: 10.1016/j.bmcl.2017.10.016.
Madeline F Long  1 ,  Julie L Engers  1 ,  Sichen Chang  1 ,  Xiaoyan Zhan  1 ,  Rebecca L Weiner  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 ,  Darren W Engers  3 ,  Craig W Lindsley  4
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 2. Vanderbilt 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 School of Medicine, Nashville, TN 37232, USA.
  • 3. Vanderbilt 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].
  • 4. Vanderbilt 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. Electronic address: [email protected].
PMID: 29037946 DOI: 10.1016/j.bmcl.2017.10.016
Abstract

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.

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