Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors
| Autor: | Casey J. N. Mathison, Mihai Azimioara, Christopher Cow, Pascal Rigollier, Ursula Bodendorf, Pierre-Yves Michellys, Victor Nikulin, Daniel Pflieger, Ben Wen, Bo Liu, Samantha Zaharevitz, Trixi Brandl, Danilo Guerini, Daniel R. Beisner, Juraj Velcicky, Robert Epple |
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| Rok vydání: | 2019 |
| Předmět: |
Myeloid
CD74 010405 organic chemistry Chemistry Organic Chemistry Substrate (chemistry) 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Transformation (genetics) Immune system medicine.anatomical_structure Orally active In vivo Drug Discovery medicine Function (biology) |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.9b00044 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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