Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu7 Positive Allosteric Modulator Tool Compound.,ACS Medicinal Chemistry Letters

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Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu7 Positive Allosteric Modulator Tool Compound.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-08-20 , DOI: 10.1021/acsmedchemlett.0c00432
Carson W Reed ₁ , Jacob J Kalbfleisch ₁ , Madison J Wong ₁ , Jordan P Washecheck ₁ , Ashton Hunter ₂ , Alice L Rodriguez _{2,

3} , Anna L Blobaum _{2,

3} , P Jeffrey Conn _{2,

3,

4} , Colleen M Niswender _{2,

3,

4} , Craig W Lindsley _{1,

2,

3}

Affiliation

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.

中文翻译：

VU6027459 的发现：一流的选择性和 CNS 渗透剂 mGlu7 正变构调节剂工具化合物。

在此，我们报告了第一个选择性和 CNS 渗透性 mGlu ₇ PAM (VU6027459) 的发现，该 PAM 源自选择性 mGlu ₇ NAM 化学型中的“分子开关”。VU6027459 在小鼠 (K _p = 2.74) 和大鼠 (K _p = 4.78) 中显示出 CNS 渗透，它在大鼠中具有口服生物利用度 (%F = 69.5)，并且在 DAT 时不需要的活性被消除。

更新日期：2020-09-10

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