Design, Synthesis, and Evaluation of the Selective and Orally Active LSD1 Inhibitor with the Potential of Treating Heart Failure

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.

赖氨酸特异性去甲基化酶1（Lysine-specific demethylase 1, LSD1）已成为开发治疗包括心力衰竭在内的心血管疾病新型药理制剂的热门靶点。本文报道了一系列靶向LSD1的TCP基衍生物的设计、合成及构效关系（Structure-Activity Relationship, SAR），并通过分子对接研究成功阐明了该系列化合物的构效规律。其中，化合物7d具备低毒性特征，在分子与细胞水平上对LSD1展现出高亲和力；其同时具备良好的口服药代动力学特性（例如生物利用度F=77.61%），可在体外有效缓解血管紧张素II（Angiotensin II, Ang II）诱导的新生大鼠心肌成纤维细胞（neonatal rat cardiac fibroblasts, NRCFs）活化，并在体内减轻主动脉弓缩窄（Transverse Aortic Constriction, TAC）诱导的心肌重构与心力衰竭模型中的病理性心肌重构。此外，机制研究显示，化合物7d对心肌功能障碍的抑制作用与LSD1抑制介导的转化生长因子β（Transforming Growth Factor β, TGFβ）信号通路活化受阻密切相关。综上，本研究表明化合物7d是一种强效的LSD1抑制剂，具备进一步开发为治疗压力超负荷相关心力衰竭治疗制剂的潜力。