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

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journal contribution
posted on 17.02.2019 by Kenneth M. Boy, Jason M. Guernon, Dmitry S. Zuev, Li Xu, Yunhui Zhang, Jianliang Shi, Lawrence R. Marcin, Mendi A. Higgins, Yong-Jin Wu, Subramaniam Krishnananthan, Jianqing Li, Ashok Trehan, Daniel Smith, Jeremy H. Toyn, Jere E. Meredith, Catherine R. Burton, S. Roy Kimura, Tatyana Zvyaga, Xiaoliang Zhuo, Kimberley A. Lentz, James E. Grace, Rex Denton, John S. Morrison, Arvind Mathur, Charles F. Albright, Michael K. Ahlijanian, Richard E. Olson, Lorin A. Thompson, John E. Macor
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 Aβ1–42 and Aβ1–40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ1–37 and Aβ1–38 were observed, with no change in the total amount of Aβ1–x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.