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. 2009 Feb 1;19(3):926-9.
doi: 10.1016/j.bmcl.2008.11.116. Epub 2008 Dec 6.

(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor

Derek C Cole  1 , Joseph R Stock, Anthony F Kreft, Madelene Antane, Suzan H Aschmies, Kevin P Atchison, David S Casebier, Thomas A Comery, George Diamantidis, John W Ellingboe, Boyd L Harrison, Yun Hu, Mei Jin, Dennis M Kubrak, Peimin Lu, Charles W Mann, Robert L Martone, William J Moore, Aram Oganesian, David R Riddell, June Sonnenberg-Reines, Shaiu-Ching Sun, Erik Wagner, Zheng Wang, Kevin R Woller, Zheng Xu, Hua Zhou, J Steven Jacobsen
Affiliations

(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor

Derek C Cole et al. Bioorg Med Chem Lett. .

Abstract

Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.

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