Discovery of a Series of Substituted 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators,Journal of Medicinal Chemistry

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Discovery of a Series of Substituted 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-09 , DOI: 10.1021/acs.jmedchem.2c01916
Christine F Gelin ₁ , Brice Stenne ₁ , Heather Coate ₁ , Afton Hiscox ₁ , Akinola Soyode-Johnson ₁ , Jessica L Wall ₁ , Brian Lord ₁ , Jeffrey Schoellerman ₁ , Kevin J Coe ₁ , Kai Wang ₁ , Jesus Alcázar ₂ , Christa C Chrovian ₁ , Curt A Dvorak ₁ , Nicholas I Carruthers ₁ , Tatiana Koudriakova ₁ , Bartosz Balana ₁ , Michael A Letavic ₁

Affiliation

Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED₅₀ of 1.7 mg/kg.

中文翻译：

发现一系列取代的 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines 作为脑渗透剂和有效的 GluN2B-选择性负变构调节剂

在此，我们将一系列取代的 1 H -((1,2,3-triazol-4-yl)methoxy)pyrimidines 描述为有效的 GluN2B 负变构调节剂。对几个五元和六元杂环的探索导致了 O-连接的嘧啶类似物的鉴定，这些类似物具有效力和理想的 ADME 特征的平衡。由于对代谢饱和度的初步观察，对化合物18 进行了早期代谢物鉴定研究，结果推动了进一步的迭代优化工作，以避免形成不需要的饱和代谢物。对 1 H -1,2,3-triazol-4-yl)methoxy)pyrimidines嘧啶部分取代的综合研究允许鉴定化合物31，它表现出高 GluN2B 受体亲和力、改善的溶解度和清洁的心血管特征。化合物31在大鼠体内以 10 mg/kg 的口服剂量进行体外靶标参与研究并获得1.7 mg/kg 的ED _{50 。}

更新日期：2023-02-09

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