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

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

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.
PMID: 39316465 DOI: 10.1021/acschemneuro.4c00465
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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