Koda Yasuko, Sato Shin, Yamamoto Hirofumi, Niwa Hideaki, Watanabe Hisami, Watanabe Chiduru, Sato Tomohiro, Nakamura Kana, Tanaka Akiko, Shirouzu Mikako, Honma Teruki, Fukami Takehiro, Koyama Hiroo, Umehara Takashi
Drug Discovery Chemistry Platform Unit, Drug Discovery Seed Compounds Exploratory Unit, Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
ACS Med Chem Lett. 2022 Apr 29;13(5):848-854. doi: 10.1021/acsmedchemlett.2c00120. eCollection 2022 May 12.
Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is ; 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 hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of 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 ) showed the most desirable activities, and its eutomer, , was isolated by the optical resolution of . In addition to potent LSD1 inhibitory activity, exhibited desirable hERG channel inhibition and microsomal stability profiles.
赖氨酸特异性去甲基化酶1（LSD1/KDM1A）是一种很有前景的癌症治疗靶点。反苯环丙胺（2-苯基环丙胺）的几种衍生物已被开发为LSD1抑制剂。其中一种衍生物是 ；然而，该化合物具有较高的人乙醚相关基因（hERG）通道抑制活性和较低的微粒体稳定性，使其不适宜作为候选药物。在此，我们使用hERG抑制预测模型，设计、合成并评估了一系列以苄氧基和哌嗪基团修饰为特征的新型衍生物。在合成的衍生物中，一种具有2-氟吡啶和2,8-二氮杂螺[4.5]癸烷基团的化合物（化合物 ）表现出最理想的活性，其优映体 通过 的光学拆分被分离出来。除了具有强大的LSD1抑制活性外， 还表现出理想的hERG通道抑制和微粒体稳定性特征。
