Discovery, SAR and Biological Evaluation of Aryl-thiazol-piperidines as SMN Modulators

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder affecting the selective degeneration of survival motor neuron (SMN) in the spinal cord due to the deletion or mutations of the survival motor neuron gene 1 (SMN1). However, the human genome includes a second nearly identical gene called SMN2 which functionally differs from SMN1 by a critical nucleotide C to T transition residing in exon 7. Although SMN2 is able to produce a small portion of full length SMN protein, the majority of SMN2 RNAs undergo alternative splicing and produce truncated, proteolytically unstable SMN variants that are not able to replace the function of full length SMN protein. Therefore, increasing overall SMN production through up-regulation of SMN2 expression or through the variation of splicing rate has been postulated to be one of the potential therapeutic strategies for SMA. In this report, we detail the discovery of ML200 (CID 46907676) as a novel arylpiperidine-based small molecule modulator of SMN protein production. ML200 had an AC50 of 31nM and gave 576% increase in fold induction of SMN promoter in the reporter assay. ML200 was confirmed by western blot analysis and gem count assay using SMA patient fibroblasts at low nanomolar range (37 nM). The structure property relationships (SPR) including microsomal stability, cell permeability and full time oral dosing in vivo pharmacokinetic studies were also investigated to address ADME properties. We anticipate that ML200 may serve as a useful lead for exploring the therapeutic benefits of SMN protein induction in SMA animal models, and ultimately in human clinical trials.