Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu7 Positive Allosteric Modulator Tool Compound

Carson W Reed; Jacob J Kalbfleisch; Madison J Wong; Jordan P Washecheck; Ashton Hunter; Alice L Rodriguez; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley

doi:10.1021/acsmedchemlett.0c00432

Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu₇ Positive Allosteric Modulator Tool Compound

ACS Med Chem Lett. 2020 Aug 20;11(9):1773-1779. doi: 10.1021/acsmedchemlett.0c00432. eCollection 2020 Sep 10.

Authors

Carson W Reed¹, Jacob J Kalbfleisch¹, Madison J Wong¹, Jordan P Washecheck¹, Ashton Hunter², Alice L Rodriguez^{3

2}, Anna L Blobaum^{3

2}, P Jeffrey Conn^{3

2

4}, Colleen M Niswender^{3

2

4}, Craig W Lindsley^{1

3

2}

Affiliations

¹ Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
² Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
³ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
⁴ Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee 37232, United States.

Abstract

Herein, we report the discovery of the first selective and CNS penetrant mGlu₇ PAM (VU6027459) derived from a "molecular switch" within a selective mGlu₇ NAM chemotype. VU6027459 displayed CNS penetration in both mice (K_p = 2.74) and rats (K_p= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.

Abstract

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