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

Abstract

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
URI:	https://oak.novartis.com/id/eprint/38774