Structure-activity relationship (SAR) studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (SRI-22819) as NF-ҡB activators for the treatment of ALS

Abstract ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the most significant finding in ALS research. SOD1 abnormalities have been associated with both familial as well as sporadic ALS cases. SOD2 is a highly inducible SOD that performs in concurrence with SOD1 to detoxify ROS. Induction of SOD2 can be obtained through activation of NF-ҡBs. We previously reported that SRI-22819 increases NF-ҡB expression and activation in vitro, but it has poor ADME properties in general and has no oral bioavailability. Our initial studies were focused on direct modifications of SRI-22819. There were active compounds identified but no improvement in microsomal stability was observed. In this context, we focused on making more significant structural changes in the core of the molecule. Ataluren, an oxadiazole compound that promotes read-through and expression of dystrophin in patients with Duchenne muscular dystrophy, bears some structural similarity to SRI-22819. Thus, we synthesized a series of SRI-22819 and Ataluren (PTC124) hybrid compounds. Several compounds from this series exhibited improved activity, microsomal stability and lower calculated polar surface area (PSA). This manuscript describes the synthesis and biological evaluation of SRI-22819 analogs and its hybrid combination with Ataluren.