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

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.

SUBMITTER: Boy KM 

PROVIDER: S-EPMC6421538 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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<sub>1-42</sub> and Aβ<sub>1-40</sub> in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ<sub>1-37</sub> and Aβ<sub>1-38</sub> were observed, with no change in the tota  ...[more]

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