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

Julie L Engers; Logan A Baker; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Colleen M Niswender; Hyekyung P Cho; Michael Bubser; Analisa Thompson Gray; Carrie K Jones; Weimin Peng; Jerri M Rook; Thomas M Bridges; Olivier Boutaud; P Jeffrey Conn; Darren W Engers; Craig W Lindsley; Kayla J Temple

doi:10.1021/acschemneuro.4c00465

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. Online ahead of print.

Authors

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 Peng², Jerri M Rook², 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).

Abstract

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