This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.

中文翻译：

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发现代谢型谷氨酸受体亚型5的4-烷氧基-6-甲基吡啶甲酸酰胺负变构调节剂。

这封信描述了VU0424238（增强剂）的进一步化学优化，VU0424238是mGlu5 NAM临床候选者，由于嘧啶头基团的物种特异性醛氧化酶（AO）代谢产物积累而在非人类灵长类动物（NHP）28天毒理学中失败。在这里，我们切除了嘧啶部分，确定了最小的药效基团，然后开发了一系列新的饱和醚头基团，这些基团消除了任何AO对代谢的贡献。该新系列中的推定后备化合物提供增强的sp3特性，跨物种的均匀CYP450介导的代谢，良好的功能效能和高的CNS渗透性。优化的关键是矩阵和迭代库的组合，可以快速监视变构配体的多个域。