Discovery, synthesis, and biological evaluation of novel SMN protein modulators.
Discovery, synthesis, and biological evaluation of novel SMN protein modulators.
复制标题
DOI：
10.1021/jm200497t
复制
发表时间：
2011-09-22
影响因子：
7.3
通讯作者：
Austin, Christopher P.
中科院分区：
文献类型：
--
作者：
Xiao, Jingbo;Marugan, Juan J.;Zheng, Wei;Titus, Steve;Southall, Noel;Cherry, Jonathan J.;Evans, Matthew;Androphy, Elliot J.;Austin, Christopher P.
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, we detail the discovery of a series of arylpiperidines as novel modulators of SMN protein. 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 (PK) studies were also investigated. We anticipate that a lead candidate chosen from this series may serve as a useful probe for exploring the therapeutic benefits of SMN protein up-regulation in SMA animal models, and a starting point for clinical development.
登录
查看更多内容
影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
30.8
作者：
Lefebvre, S;Burlet, P;Melki, J
通讯作者：
Melki, J
影响因子：
15.9
作者：
Avila, Amy M.;Burnett, Barrington G.;Sumner, Charlotte J.
通讯作者：
Sumner, Charlotte J.
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G