Velcicky, Juraj, Bodendorf, Ursula, Rigollier, Pascal, Epple, Robert, Beisner, Daniel, Guerini, Danilo, Smith, Philip, Liu, Bo, Feifel, Roland, Wipfli, Peter, Aichholz, Reiner, Couttet, Philippe, Dix, Ina, Widmer, Toni, Wen, Ben and Brandl, Trixi (2018) Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo. Journal of Medicinal Chemistry, 61 (3). pp. 865-880. ISSN 0022-26231520-4804

Abstract

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.

Item Type:	Article
Date Deposited:	24 Feb 2018 00:45
Last Modified:	24 Feb 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34024