Discovery of a novel selenamide derivative as potent activator of aldehyde dehydrogenase 2 for cardioprotective applications

Abstract

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a pivotal role in the metabolism of endogenous reactive aldehydes and functions as a crucial defense mechanism against oxidative stress. The inactive ALDH2 rs671 polymorphism has been implicated in an elevated risk of various cardiovascular diseases, such as myocardial infarction, cardiac arrhythmia, coronary heart disease, and heart failure. Alda-1 is currently the most widely recognized ALDH2 activator and its anti-heart failure properties have been extensively reported. However, Alda-1 possesses limitations in terms of pharmacokinetic properties, safety, and bioavailability, which hinder its broad clinical application. Therefore, the development of novel ALDH2 activators represents a promising novel therapeutic approach. In this study, we employed a bioisosteric substitution strategy to modify the amide bond of Alda-1. Consequently, a selenamide derivative A8 was discovered to exhibit potent ALDH2 activation activity at the submicromolar level (ALDH2*1: EC₅₀ = 0.21 ± 0.03 μM; ALDH2*2: EC₅₀ = 0.31 ± 0.03 μM) and showed reduced cytotoxicity compared to Alda-1 in H9c2 and HepG2 cell lines. Furthermore, A8 provided potent protection of cardiomyocytes and showed enhanced efficiency in metabolizing endogenous reactive aldehydes. Our findings present A8 as a valuable lead compound for advancing the development of ALDH2 activators, thereby offering new avenues for cardioprotective therapies.