Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
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DOI：
10.1021/acsmedchemlett.8b00541
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发表时间：
2019-03-01
影响因子：
4.2
通讯作者：
Macor, John E.
中科院分区：
文献类型：
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作者：
Boy, Kenneth M.;Guernon, Jason M.;Macor, John E.
从BMS化合物集合的筛选中鉴定的三氮杂环命中化合物针对效力、体内活性和脱靶情况进行了优化，以生产双环嘧啶伽马分泌酶调节剂BMS-932481。该化合物显示出在小鼠和大鼠的血浆、脑和脑脊液中Aβ(1-42)和Aβ(1-40)的显著降低。与伽马分泌酶调节机制一致，观察到Aβ(1-37)和Aβ(1-38)的增加，而Aβ(1-x)的产生总量没有变化。没有观察到基于Notch的毒性，BMS-932481的总体临床前概况支持其在人类临床试验中的进一步评估。
A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine gamma-secretase modulator BMS-932481. The compound showed robust reductions of A beta(1-42) and A beta(1-40) in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the gamma-secretase modulator mechanism, increases in A beta(1-37) and A beta(1-38) were observed, with no change in the total amount of A beta(1-x) produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.