• Bioorg. Med. Chem. · Dec 2009

    Structural optimization of a CXCR2-directed antagonist that indirectly inhibits gamma-secretase and reduces Abeta.

    • Pancham Bakshi, Chao Jin, Pierre Broutin, Beniam Berhane, Jon Reed, and Michael Mullan.
    • Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, United States. pbakshi@rfdn.org
    • Bioorg. Med. Chem. 2009 Dec 1; 17 (23): 8102-12.

    AbstractAmyloid beta (Abeta), a key molecule in the pathogenesis of Alzheimer's disease (AD), is derived from the amyloid precursor protein (APP) by sequential proteolysis via beta- and gamma-secretases. Because of their role in generation of Abeta, these enzymes have emerged as important therapeutic targets for AD. In the case of gamma-secretase, progress has been made towards designing potent inhibitors with suitable pharmacological profiles. Direct gamma-secretase inhibitors are being evaluated in clinical trials and new strategies are being explored to block gamma-secretase activity indirectly as well. In this regard, we have previously reported an indirect regulation of gamma-secretase through antagonism of CXCR2, a G-protein coupled receptor (GPCR). We demonstrated that N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea (SB225002), a selective inhibitor of CXCR2 also plays a role in an indirect inhibition of gamma-secretase. Furthermore, we reported a approximately 5-fold difference in the selective inhibition of APP versus Notch processing via gamma-secretase following treatment with SB225002. Herein we describe the synthesis and optimization of SB225002. By determination of the structure-activity relationship (SAR), we derived small molecules that inhibit Abeta40 production with IC(50) values in the sub-micromolar range in a cell-based assay and also validated the potential of CXCR2 as a new target for therapeutic intervention in AD.

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