1. Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
- Author
-
John E. Macor, Yunhui Zhang, James E. Grace, Lorin A. Thompson, Jeremy H. Toyn, Lawrence R. Marcin, Subramaniam Krishnananthan, Jianliang Shi, Dmitry Zuev, Daniel Smith, Jianqing Li, Yong-Jin Wu, Jason M. Guernon, Xiaoliang Zhuo, Tatyana Zvyaga, Xu Li, Arvind Mathur, John Morrison, Jere E. Meredith, Charles F. Albright, S. Roy Kimura, Mendi A. Higgins, Kimberley A. Lentz, Richard E. Olson, Rex Denton, Kenneth M. Boy, Catherine R. Burton, Ashok K. Trehan, and Michael K. Ahlijanian
- Subjects
gamma-secretase modulator ,Letter ,Bicyclic molecule ,Pyrimidine ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,bicyclic pyrimidine ,clinical candidate ,γ secretase modulator ,Pharmacology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Cerebrospinal fluid ,In vivo ,Drug Discovery ,Toxicity ,Potency ,Alzheimer’s disease ,Triazine - 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 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.
- Published
- 2019