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Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors

Velcicky, Juraj, Mathison, Casey, Nikulin, Victor, Pflieger, Daniel, Epple, Robert, Azimioara, Mihai, Cow, Christopher, Michellys, Pierre, Rigollier, Pascal, Beisner, Daniel, Bodendorf, Ursula, Guerini, Danilo, Liu, Bo, Wen, Ben, Zaharevitz, Samantha and Brandl, Trixi (2019) Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors. ACS Medicinal Chemistry Letters, 10. ISSN 1948-58751948-5875


SPPL2a (Signal Peptide Peptidase Like 2a) is an intramembrane aspartyl protease engaged in the function of B-cells and dendritic cells. Despite being an attractive target for modulation of the immune system, selective SPPL2a
inhibitors are barely described in the literature. Recently, we have disclosed a selective, small molecular weight agent SPL‑707 which confirmed that pharmacological inhibition of SPPL2a leads to the accumulation of its substrate CD74/p8 and as a consequence to a reduction in the number of B-cells as well as myeloid dendritic cells in mice. In this paper we describe the discovery of novel hydroxyethylamine based SPPL2a inhibitors. Starting from a rather lipophilic screening hit, several iterative optimization cycles allowed for its transformation into a highly potent and selective compound 15 (SPL-410) which inhibited in vivo CD74/p8 fragment processing in mice at 10 mg/kg oral dose.

Item Type: Article
Keywords: SPPL2a, CD74, hydroxyethylamine, sulfonamide, inhibitor, oral activity
Date Deposited: 15 Jun 2019 00:45
Last Modified: 15 Jun 2019 00:45