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.