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Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo.
Velcicky, Juraj; Bodendorf, Ursula; Rigollier, Pascal; Epple, Robert; Beisner, Daniel R; Guerini, Danilo; Smith, Philip; Liu, Bo; Feifel, Roland; Wipfli, Peter; Aichholz, Reiner; Couttet, Philippe; Dix, Ina; Widmer, Toni; Wen, Ben; Brandl, Trixi.
Afiliação
  • Epple R; The Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • Beisner DR; The Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • Liu B; The Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • Widmer T; Chemical and Pharmaceutical Profiling, Global Drug Development, Novartis Pharma AG , CH-4002 Basel, Switzerland.
  • Wen B; The Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
J Med Chem ; 61(3): 865-880, 2018 02 08.
Article em En | MEDLINE | ID: mdl-29359565
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.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Ácido Aspártico Endopeptidases / Fatores Imunológicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Ácido Aspártico Endopeptidases / Fatores Imunológicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2018 Tipo de documento: Article