3 years ago

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

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

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01371

DOI: 10.1021/acs.jmedchem.7b01371

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