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默沙东阿尔茨海默氏症药物Verubecestat(MK-8931)的合成  

2015-07-16 15:15:25|  分类: 合成化学 |  标签: |举报 |字号 订阅

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默沙东阿尔茨海默氏症药物Verubecestat(MK-8931)的合成方法 Synthesis of Verubecestat (MK-8931), Merck’s Novel Drug For Alzheimer’s Disease

Verubecestat(MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE)1 and BACE2 in development by Merck for the treatment of Alzheimer’s Disease.

默沙东阿尔茨海默氏症药物Verubecestat(MK-8931)的化学结构 Chemical Structure of Verubecestat(MK-8931), Merck’s BACE Inhibitor for Alzheimer’s Disease

Chemical Structure of Verubecestat(MK-8931), Merck's BACE Inhibitor for Alzheimer's Disease 默沙东阿尔茨海默氏症药物Verubecestat(MK-8931)的化学结构The rationale of BACE inhibition is that it represents an upstream interference with the amyloid cascade and reduces cleavage of APP that leads to Aβ production. In April 2012, Phase I data on inhibitor MK-8931 was presented. This drug reduced Aβ CSF levels up to 92% and was well tolerated by patients [26]. In March 2013, data was added from a 1 week trial in 32 mild to moderate AD patients, showing CSF Aβ levels decreased up to 84% . In 2012, Merck launched the EPOCH trial, an 18-month Phase II/III trial comparing 12, 40, or 60 mg/day of MK-8931 given as once-daily tablets to placebo in patients with mild to moderate AD. The trial includes conventional cognitive and functional primary outcomes, as well as sub-studies for biomarker outcomes indicating change in brain amyloid and CSF tau levels, as well as change in brain volume. Further, in 2013, Merck began the APECS trial in 1,500 participants with prodromal AD. These patients have measureable cognitive deficits and a positive PET scan with the newly FDA-approved amyloid tracer flutemetamol, but are not functionally impaired. APECS will compare the 12- and 40-mg once-daily dose to placebo over 24 months.

默沙东阿尔茨海默氏症药物Verubecestat(MK-8931)的合成方法 Synthesis of Verubecestat (MK-8931), Merck’s BACE Inhibitor for Alzheimer’s Disease

Synthesis of Verubecestat (MK-8931), Merck's BACE Inhibitor for Alzheimer's Disease 默沙东阿尔茨海默氏症药物Verubecestat(MK-8931)的合成方法

Sources:

Forman M, Tseng J, Palcza J, Leempoels J, Ramael S, Krishna G. The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid peptides in healthy subjects: results from a rising single dose study (PL02. 004). 64th American Academy of Neurology Annual Meeting. Neurology, New Orleans; 2012. OpenURL

Forman MS PJ, Tseng J, Dockendorf M, Canales C, Apter J, Backonja M, et al. The novel BACe inhibitor MK-8931 dramatically lowers CSF Abeta peptide in patients with mild to moderate Alzheimer’s disease. In: The 11th International Conference on Alzheimer’s and Parkinson’s Disease. Florence, Italy. 2013.

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