Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM)

  • ACS Chem Neurosci. 2024 Sep 24;15(20):3744-3754. doi: 10.1021/acschemneuro.4c00465.
Julie L Engers  1  2 Logan A Baker  1  2 Sichen Chang  1  2 Vincent B Luscombe  1  2 Alice L Rodriguez  1  2 Colleen M Niswender  1  2  3  4 Hyekyung P Cho  1  2 Michael Bubser  1  2 Analisa Thompson Gray  1  2 Carrie K Jones  1  2 Weimin Peng  2 Jerri M Rook  2 Thomas M Bridges  1  2 Olivier Boutaud  1  2 P Jeffrey Conn  1  2  3 Darren W Engers  1  2 Craig W Lindsley  1  2  5  6 Kayla J Temple  1  2
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3. Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 4. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 5. Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
Abstract

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace a 5-amino-2,4-dimethylthieno[2,3-d]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M4 and were highly brain-penetrant, the 2,4-dimethylpyrido[4',3':4,5]thieno[2,3-d]pyrimidine tricycle core provided lead compound, VU6016235, with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.

Keywords
Alzheimer’s disease; Muscarinic acetylcholine receptor (mAChR); Muscarinic acetylcholine receptor subtype 4 (M4); Parkinson’s disease; Positive allosteric modulator (PAM); Schizophrenia; Structure−activity relationship (SAR).
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