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Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

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    Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease
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    ‡ †Department of Medicinal Chemistry, ‡Department of Neuroscience, ∥Department of Pharmaceutical Sciences, and §Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
    *Phone: 732-594-2987. Fax: 732-594-3007. E-mail: [email protected]
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2012, 3, 11, 892–896
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    https://doi.org/10.1021/ml300044f
    Published April 9, 2012
    Copyright © 2012 American Chemical Society
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    Abstract

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    An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (−)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (−)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer’s disease.

    Copyright © 2012 American Chemical Society

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    Supporting Information

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    Experimental details for synthetic procedures and compound characterization for compounds 5–24 and crystallographic data of compound (−)-16. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 13 publications.

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    10. Wen-Lian Wu, Duane A. Burnett, John Clader, William J. Greenlee, Qin Jiang, Lynn A. Hyde, Robert A. Del Vecchio, Mary E. Cohen-Williams, Lixin Song, Julie Lee, Giuseppe Terracina, Qi Zhang, Amin Nomeir, Eric M. Parker, Lili Zhang. Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors. Bioorganic & Medicinal Chemistry Letters 2016, 26 (23) , 5836-5841. https://doi.org/10.1016/j.bmcl.2016.04.095
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2012, 3, 11, 892–896
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ml300044f
    Published April 9, 2012
    Copyright © 2012 American Chemical Society
    Request reuse permissions

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