Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series. Investigation of a database of chemicals tested in these systems and transcriptional profiling suggested that the mechanism of toxicity may involve modulation of nuclear receptor targets RAR/RXR, and/or VDR with AhR antagonism. The studies reported here demonstrate how phenotypic profiling of preclinical drug candidates using human primary cells can provide insights into the mechanisms of toxicity and inform early drug discovery and development campaigns.

中文翻译：

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代谢型谷氨酸受体5负变构调节剂与皮肤毒性的机制。

皮肤反应代表在临床试验中观察到的最常见的药物不良反应之一，可导致大量化合物磨损。由辉瑞公司开发的，代表神经系统疾病重要靶点的代谢型谷氨酸受体（mGluRs）的三种负变构调节剂（NAM），由于在非人灵长类动物（NHPs）中观察到的IV型皮肤超敏反应迟缓，最近在临床前开发中均告失败。 。在这里，我们在人类原代细胞/共培养系统的标准化面板中采用了大规模的表型分析，以表征来自两个不同系列的mGluR5 NAM的皮肤毒性机制。对在这些系统中测试过的化学物质和转录谱进行的数据库研究表明，毒性机理可能涉及核受体RAR / RXR的调节，和/或具有AhR拮抗作用的VDR。此处报道的研究表明，使用人类原代细胞进行临床前候选药物的表型分析可如何提供毒性机制的见解，并为早期的药物发现和开发活动提供信息。