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首个直接作用的快速骨骼肌肌钙蛋白激活剂的发现。

Discovery of , the First Direct Fast Skeletal Muscle Troponin Activator.

作者信息

Collibee Scott E, Bergnes Gustave, Muci Alexander, Browne William F, Garard Marc, Hinken Aaron C, Russell Alan J, Suehiro Ion, Hartman James, Kawas Raja, Lu Pu-Ping, Lee Kenneth H, Marquez David, Tomlinson Matthew, Xu Donghong, Kennedy Adam, Hwee Darren, Schaletzky Julia, Leung Kwan, Malik Fady I, Morgans David J, Morgan Bradley P

机构信息

Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States.

出版信息

ACS Med Chem Lett. 2018 Feb 13;9(4):354-358. doi: 10.1021/acsmedchemlett.7b00546. eCollection 2018 Apr 12.

DOI:10.1021/acsmedchemlett.7b00546
PMID:29670700
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5900333/
Abstract

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.

摘要

首次报道了快速骨骼肌的首批激活剂的鉴定和优化。化合物通过高通量筛选（HTS）被鉴定出来，随后发现其通过与肌钙蛋白复合物相互作用来改善肌肉功能。对该化合物的效力、代谢稳定性和物理性质进行优化后，发现了替拉西泮（tirasemtiv），它在治疗肌萎缩侧索硬化症的临床试验中已得到广泛表征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/c2bcd5ce63bf/ml-2017-00546m_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/34ee2f679e54/ml-2017-00546m_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/48151439b6ce/ml-2017-00546m_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/c432e73ba8ea/ml-2017-00546m_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/c2bcd5ce63bf/ml-2017-00546m_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/34ee2f679e54/ml-2017-00546m_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/48151439b6ce/ml-2017-00546m_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/c432e73ba8ea/ml-2017-00546m_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23de/5900333/c2bcd5ce63bf/ml-2017-00546m_0003.jpg

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