Concepedia

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Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481

DOIFull Paper Access

22

Citations

18

References

2019

Year

Kenneth M. Boy, Jason Guernon, Dmitry Zuev, Li Xu, Yunhui Zhang, Jianliang Shi, Lawrence R. Marcin, Mendi A. Higgins, Yong‐Jin Wu, Subramaniam Krishnananthan,
ACS Medicinal Chemistry Letters

Abstract

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 γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ<sub>1-42</sub> and Aβ<sub>1-40</sub> in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ<sub>1-37</sub> and Aβ<sub>1-38</sub> were observed, with no change in the total amount of Aβ<sub>1-<i>x</i></sub> produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.

References

YearCitations

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