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

Autor: Boy KM; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Guernon JM; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Zuev DS; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Xu L; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Zhang Y; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Shi J; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Marcin LR; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Higgins MA; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Wu YJ; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Krishnananthan S; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Li J; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Trehan A; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Smith D; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Toyn JH; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Meredith JE; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Burton CR; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Kimura SR; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Zvyaga T; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Zhuo X; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Lentz KA; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Grace JE; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Denton R; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Morrison JS; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Mathur A; Bristol-Myers Squibb, Princeton, New Jersey 08543, United States., Albright CF; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Ahlijanian MK; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Olson RE; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Thompson LA; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States., Macor JE; Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 Feb 17; Vol. 10 (3), pp. 312-317. Date of Electronic Publication: 2019 Feb 17 (Print Publication: 2019).
DOI: 10.1021/acsmedchemlett.8b00541
Abstrakt: 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 1-42 and Aβ 1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ 1-37 and Aβ 1-38 were observed, with no change in the total amount of Aβ 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.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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