Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Elizabeth S Childress; Rory A Capstick; Katherine E Crocker; Miranda L Ledyard; Aaron M Bender; Mallory A Maurer; Natasha B Billard; Hyekyung P Cho; Alice L Rodriguez; Colleen M Niswender; Weimin Peng; Jerri M Rook; Sichen Chang; Anna L Blobaum; Olivier Boutaud; Analisa Thompson Gray; Carrie K Jones; P Jeffrey Conn; Andrew S Felts; Craig W Lindsley; Kayla J Temple

doi:10.1021/acsmedchemlett.4c00481

Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

ACS Med Chem Lett. 2024 Nov 18;15(12):2210-2219. doi: 10.1021/acsmedchemlett.4c00481. eCollection 2024 Dec 12.

Authors

Elizabeth S Childress^{1

2}, Rory A Capstick^{1

2}, Katherine E Crocker^{1

2}, Miranda L Ledyard^{1

2}, Aaron M Bender^{1

2}, Mallory A Maurer^{1

2}, Natasha B Billard^{1

2}, Hyekyung P Cho^{1

2}, Alice L Rodriguez^{1

2}, Colleen M Niswender^{1

2

3

4

5}, Weimin Peng², Jerri M Rook², Sichen Chang^{1

2}, Anna L Blobaum^{1

2}, Olivier Boutaud^{1

2}, Analisa Thompson Gray^{1

2}, Carrie K Jones^{1

2

5}, P Jeffrey Conn^{1

2

5}, Andrew S Felts^{1

2}, Craig W Lindsley^{1

2

6

3}, 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 Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
⁴ Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
⁵ Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
⁶ Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.

Abstract

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu₅) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified VU6043653, a highly brain penetrant and selective mGlu₅ NAM which displayed moderate potency against both human and rat mGlu₅. Moreover, VU6043653 has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, VU6043653 exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.