2. Academic Validation
  3. Discovery of Pre-Clinical Candidate VU6008055/ AF98943: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy

Discovery of Pre-Clinical Candidate VU6008055/ AF98943: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy

  • ACS Chem Neurosci. 2025 Jun 4;16(11):2141-2162. doi: 10.1021/acschemneuro.5c00277.
Julie L Engers 1 2,  Sean R Bollinger 1 2,  Alison R Gregro 1 2,  Rory A Capstick 1 2,  Paul K Spearing 1 2,  Madeline F Long 1 2,  James C Tarr 1 2,  Katherine J Watson 1 2,  Sichen Chang 1 2,  Vincent B Luscombe 1 2,  Alice L Rodriguez 1 2,  Hyekyung P Cho 1 2,  Aidong Qi 1 2,  Colleen M Niswender 1 2 3 4,  Michael Bubser 1 2,  Robert W Gould 1 2,  William Hudson Robb 1 2,  Nellie Byun 1 2 5,  John Gore 5 6 7,  Carrie K Jones 1 2 4,  Morten S Thomsen 8,  Thomas M Bridges 1 2,  Olivier Boutaud 1 2,  P Jeffrey Conn 1 2 4,  Darren W Engers 1 2,  Craig W Lindsley 1 2 9 10,  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 Vanderbilt University Institute of Imaging Science, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6 Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 7 Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 8 Neuroscience Research, H. Lundbeck A/S, Valby DK-2500, Denmark.
  • 9 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 10 Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 40415588 DOI: 10.1021/acschemneuro.5c00277
Abstract

Herein, we report the structure-activity relationship to develop novel tricyclic M4 positive allosteric modulator scaffolds with improved pharmacological properties. This endeavor involved modifying a 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxamide core via a "tie-back" strategy to discover a novel tricyclic 3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazine core. From this exercise, VU6008055/AF98943 was identified as a preclinical candidate, which displays low nanomolar potency against both human and rat M4. Moreover, VU6008055 is highly brain penetrant, has an overall superior pharmacological and DMPK profile to previously reported M4 PAMs, and demonstrates efficacy in preclinical models of antipsychotic-like activity.

Keywords

Alzheimer’s disease; M4; Parkinson’s disease; VU6008055; muscarinic acetylcholine receptor (mAChR); positive allosteric modulator (PAM); schizophrenia; structure–activity relationship (SAR).

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