LSD1 has become an appealing target for the development of new pharmacologic agents to treat cardiovascular diseases, including heart failure. Herein, we reported the design, synthesis, and structure–activity relationship of a series of TCP-based derivatives targeting LSD1. Docking studies were employed to successfully elucidate the SAR. Particularly, compound 7d, characterized by low toxicity, demonstrated a high affinity for LSD1 at molecular and cellular levels. It also displayed favorable pharmacokinetic properties for oral dosing (e.g., F = 77.61%), effectively alleviating Ang II-induced NRCFs activation in vitro and reducing pathological myocardial remodeling in TAC-induced cardiac remodeling and heart failure in vivo. Additionally, mechanism studies revealed that suppression of myocardial dysfunction by compound 7d is related to LSD1 inhibition-induced TGFβ signaling pathway repressing. In summary, the current report presents compound 7d as a potent LSD1 inhibitor with the potential for further development as a therapeutic agent for pressure overload-related heart failure.

中文翻译：

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具有治疗心力衰竭潜力的选择性口服活性 LSD1 抑制剂的设计、合成和评估


LSD1 已成为开发治疗心血管疾病（包括心力衰竭）的新药物的一个有吸引力的目标。在此，我们报道了一系列基于 TCP 的针对 LSD1 的衍生物的设计、合成和构效关系。通过对接研究成功阐明了 SAR。特别是，化合物7d具有低毒性，在分子和细胞水平上表现出对LSD1的高亲和力。它还显示出口服给药良好的药代动力学特性（例如，F = 77.61%），在体外有效减轻Ang II诱导的NRCFs激活，并在体内减少TAC诱导的心脏重塑和心力衰竭中的病理性心肌重塑。此外，机制研究表明，化合物7d对心肌功能障碍的抑制与LSD1抑制诱导的TGFβ信号通路抑制有关。总之，本报告提出化合物 7d 作为一种有效的 LSD1 抑制剂，具有进一步开发作为压力超负荷相关心力衰竭治疗剂的潜力。