Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fast-progressing disease characterized by the loss of voluntary movements and death due to respiratory failure. The presence of protein aggregates is a major hallmark of the disease. Hence, targeting the pathological protein aggregation may provide more efficient therapeutics for ALS. Recently, we reported a cyclohexane-1,3-dione (NU-9) with in vitro anti-aggregation capacity and promising in vivo efficacy in ALS animal models, which validated our approach toward the development of novel and potentially more effective ALS therapeutics. Herein, we report the design and synthesis of a new series of small-molecule derivatives of NU-9 and the evaluation of their in vitro anti-aggregation activity in a PC12 cellular model containing an SOD1G85R familial ALS mutation. The most promising compound (20) presented an in vitro anti-aggregation potency comparable to that of NU-9. Moreover, the better in vitro BBB permeability, microsomal stability, and toxicity profile of 20 also suggests a potentially higher efficacy in vivo.