Xiao, Jingbo published the artcileDiscovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators, Recommanded Product: Morpholine-4-carbothioamide, the publication is Journal of Medicinal Chemistry (2011), 54(18), 6215-6233, database is CAplus and MEDLINE.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting the expression or function of survival motor neuron protein (SMN) due to the homozygous deletion or rare point mutations in the survival motor neuron gene 1 (SMN1). The human genome includes a second nearly identical gene called SMN2 that is retained in SMA. SMN2 transcripts undergo alternative splicing with reduced levels of SMN. Up-regulation of SMN2 expression, modification of its splicing, or inhibition of proteolysis of the truncated protein derived from SMN2 have been discussed as potential therapeutic strategies for SMA. In this manuscript, the discovery of a series of arylpiperidines as novel modulators of SMN protein is described. Systematic hit-to-lead efforts significantly improved potency and efficacy of the series in the primary and orthogonal assays. Structure-property relationships including microsomal stability, cell permeability, and in vivo pharmacokinetics were also investigated. In consideration to all the aspects including ADME properties, the analogs I (X = NH2, R = 3-i-PrOC6H4; X = OH, R = 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl) possessed the best combination of potency, efficacy, mouse liver microsomal stability and cell permeability as well as good oral absorption and CNS penetration upon oral gavage administration. These compounds also showed no sign of toxicity or behavioral disturbance in animals.
Journal of Medicinal Chemistry published new progress about 14294-10-1. 14294-10-1 belongs to amides-buliding-blocks, auxiliary class Morpholine,Thiourea,Amine,Amide, name is Morpholine-4-carbothioamide, and the molecular formula is C12H10N2O5, Recommanded Product: Morpholine-4-carbothioamide.
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