Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles
Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles
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DOI：
10.1021/acsmedchemlett.2c00120
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发表时间：
2022-05-12
影响因子：
4.2
通讯作者：
Umehara, Takashi
中科院分区：
文献类型：
--
作者：
Koda, Yasuko;Sato, Shin;Umehara, Takashi
赖氨酸特异性去甲基化酶1（LSD 1/KDM 1A）是一种很有前途的肿瘤治疗靶点。反苯环丙胺（反式-2-苯基环丙胺）的几种衍生物已被开发为LSD 1抑制剂。一种这样的衍生物是S2157;然而，该化合物具有高hERG通道抑制活性和低微粒体稳定性，使其不适合作为候选药物。在这里，使用在丝（）hERG抑制预测模型，我们设计，合成，并评估了一系列新的S2157衍生物，其特征在于苄氧基和哌嗪基团的修饰。在所合成的衍生物中，具有2-氟吡啶和2，8-二氮杂螺[4.5]癸烷基团的化合物（化合物10）显示出最理想的活性，并且通过10的光学拆分分离其优对映体S1427。除了有效的LSD 1抑制活性外，S1427还表现出理想的hERG通道抑制和微粒体稳定性特征。
Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (trans-2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is S2157; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Here, using an in silk() hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of S2157 derivatives characterized by modifications of the benzyloxy and piperazine groups. Among the synthesized derivatives, a compound possessing 2-fluoropyridine and 2,8-diaza-spiro[4.5]decane groups (compound 10) showed the most desirable activities, and its eutomer, S1427, was isolated by the optical resolution of 10. In addition to potent LSD1 inhibitory activity, S1427 exhibited desirable hERG channel inhibition and microsomal stability profiles.