2. Academic Validation
  3. Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors

Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors

  • ACS Med Chem Lett. 2019 May 23;10(6):887-892. doi: 10.1021/acsmedchemlett.9b00044.
Juraj Velcicky 1,  Casey J N Mathison 2,  Victor Nikulin 2,  Daniel Pflieger 1,  Robert Epple 2,  Mihai Azimioara 2,  Christopher Cow 2,  Pierre-Yves Michellys 2,  Pascal Rigollier 1,  Daniel R Beisner 2,  Ursula Bodendorf 1,  Danilo Guerini 1,  Bo Liu 2,  Ben Wen 2,  Samantha Zaharevitz 2,  Trixi Brandl 1
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, and Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  • 2 The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
PMID: 31223443 DOI: 10.1021/acsmedchemlett.9b00044
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.

Figures
Products