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ACS Med Chem Lett. 2019 Feb 17;10(3):312-317. doi: 10.1021/acsmedchemlett.8b00541. eCollection 2019 Mar 14.

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

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Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States.
Bristol-Myers Squibb, Princeton, New Jersey 08543, United States.


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.

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