Identification and Preclinical Evaluation of the Bicyclic Pyrimidine ?-Secretase Modulator BMS-932481
Kenneth M. Boy, Jason M. Guernon, Dmitry Zuev, Li Jing Xu, Yunhui Zhang, Jianliang Shi, Lawrence R. Marcin, Mendi A. Higgins, Yong‐Jin Wu, Subramaniam Krishnananthan, Jianqing Li, Ashok K. Trehan, Daniel Smith, Jeremy H. Toyn, Jere E. Meredith, Catherine R. Burton, S. Roy Kimura, Tatyana A. Zvyaga, Xiaoliang Zhuo, Kimberley A. Lentz · ACS Medicinal Chemistry Letters · 2019
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 ?-secretase modulator BMS-932481. The compound showed robust reductions of A?1?42 and A?1?40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the ?-secretase modulator mechanism, increases in A?1?37 and A?1?38 were observed, with no change in the total amount of A?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.