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

[Image: see text] 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(1–42) and Aβ(1–40) in the plas...

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Detalles Bibliográficos
Autores principales: Boy, Kenneth M., Guernon, Jason M., Zuev, Dmitry S., Xu, Li, Zhang, Yunhui, Shi, Jianliang, Marcin, Lawrence R., Higgins, Mendi A., Wu, Yong-Jin, Krishnananthan, Subramaniam, Li, Jianqing, Trehan, Ashok, Smith, Daniel, Toyn, Jeremy H., Meredith, Jere E., Burton, Catherine R., Kimura, S. Roy, Zvyaga, Tatyana, Zhuo, Xiaoliang, Lentz, Kimberley A., Grace, James E., Denton, Rex, Morrison, John S., Mathur, Arvind, Albright, Charles F., Ahlijanian, Michael K., Olson, Richard E., Thompson, Lorin A., Macor, John E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421538/
https://www.ncbi.nlm.nih.gov/pubmed/30891132
http://dx.doi.org/10.1021/acsmedchemlett.8b00541
Descripción
Sumario:[Image: see text] 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(1–42) and Aβ(1–40) in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ(1–37) and Aβ(1–38) were observed, with no change in the total amount of Aβ(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.

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