Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo

Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selecti...

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Published in:Journal of medicinal chemistry 2018-02, Vol.61 (3), p.865-880
Main Authors: Velcicky, Juraj, Bodendorf, Ursula, Rigollier, Pascal, Epple, Robert, Beisner, Daniel R, Guerini, Danilo, Smith, Philip, Liu, Bo, Feifel, Roland, Wipfli, Peter, Aichholz, Reiner, Couttet, Philippe, Dix, Ina, Widmer, Toni, Wen, Ben, Brandl, Trixi
Format: Article
Language:English
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Summary:Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selective and orally active SPPL2a inhibitor (S)-2-cyclopropyl-N1-((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro­[benzo­[d]­pyrazolo­[1,2-a]­[1,2]­diazepine-2,1′-cyclopropan]-10-yl)-N4-(5-fluoro-2-methylpyridin-3-yl)­succinamide 40 (SPL-707). This compound shows adequate selectivity against the closely related enzymes γ-secretase and SPP and a good pharmacokinetic profile in mouse and rat. Compound 40 significantly inhibited processing of the SPPL2a substrate CD74/p8 fragment in rodents at doses ≤10 mg/kg b.i.d. po. Oral dosing of 40 for 11 days at ≥10 mg/kg b.i.d. recapitulated the phenotype seen in Sppl2a knockout (ko) and ENU mutant mice (reduced number of specific B cells and myeloid dendritic cells). Thus, we believe that SPPL2a represents an interesting and druggable pharmacological target, potentially providing a novel approach for the treatment of autoimmune diseases by targeting B cells and dendritic cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01371