Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors

Velcicky, Juraj; Mathison, Casey J. N.; Nikulin, V. I.; Pflieger, Daniel; Epple, Robert; Azimioara, Mihai; Cow, Christopher; Michellys, Pierre‐Yves; Rigollier, Pascal; Beisner, Daniel R.; Bodendorf, Ursula; Guerini, Danilo; Liu, Bo; Wen, Ben G.; Zaharevitz, Samantha; Brandl, Trixi

doi:10.1021/acsmedchemlett.9b00044

Cited by 10 publications

(15 citation statements)

References 25 publications

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“…HEAs. The standard procedures for ring opening of the epoxide, 1 have been optimized that led to regioselective HEA analogs identified as scaffolds potent against malaria parasite [28][29][30] , plasmepsin inhibitors [31][32][33] , HIV inhibitors [34][35] etc.As a part of our ongoing research interest towards the search of new HEA scaffolds, synthesis of these analogs based on epoxide 1 was attempted following the standard conventional synthetic routes. Initially, ring opening reaction of epoxide 1 (1.0 mmol), with ptoluidine, 2a (1.0 mmol) in iso-propanol (50 mL) was carried out for 12 hours at 80 o C as reported in the literature [36] however, thin layer chromatography (TLC) did not indicate any product formation.…”

Section: Resultsmentioning

confidence: 99%

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Catalyst Free, Nitromethane Assisted Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines

Kumar¹,

Bansal²,

Upadhyay³

et al. 2020

Preprint

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<p>Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, a convenient, green and highly efficient regioselective ring opening of sterically hindered (2R,3S)-3-(<i>N</i>-Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involves reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new β-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41-98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR and UV-visible spectroscopic studies suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent and simple workup procedures.</p>

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Section: Resultsmentioning

confidence: 99%

“…Energies, geometrical, surface and charge characteristics were calculated within MERA model. [29][30][31] -butyl (3-hydroxy-1-phenyl-4-(p-tolylamino)butan-2-yl)carbamate (3a):…”

Section: Computationalmentioning

confidence: 99%

Catalyst Free, Nitromethane Assisted Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines

Kumar¹,

Bansal²,

Upadhyay³

et al. 2020

Preprint

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“…By variation of the different substituents, the IC 50 in a cell-based SPPL2a assay could be lowered from 4.3 to 0.009 µM of the optimised compound SPL-410. IC 50 values against γ-secretase, SPP and SPPL2b were around 1.3 µM, 0.65 µM and 0.27 µM, respectively, indicating a certain selectivity of this compound for SPPL2a [112]. However, the activity of SPL-410 against SPPL2c and SPPL3 has not been reported yet.…”

Section: Recent Advances In Spp/sppl Inhibitor Developmentmentioning

confidence: 91%

“…In general, oral application of a single dose (10 mg/kg body weight) of SPL-410 to mice was able to induce the accumulation of the CD74 NTF in the spleen. However, a rather high plasma protein binding limits the potency and applicability of this inhibitor in vivo making further rounds of optimisations necessary [112].…”

Section: Recent Advances In Spp/sppl Inhibitor Developmentmentioning

confidence: 99%

“…Based on the growing interest in inhibition of SPP/SPPL protease family members especially for the modulation of the adaptive immune system but also for treatment of viral and plasmodium infections, a substantial effort was invested in the generation of small molecule inhibitors for these proteases [ 110 – 112 ]. This process significantly profited from existing compounds initially generated for inhibition of the related γ-secretase for treatment of Alzheimer’s disease and leukaemia [ 113 ].…”

Section: Recent Advances In Spp/sppl Inhibitor Developmentmentioning

confidence: 99%

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Physiological functions of SPP/SPPL intramembrane proteases

Mentrup

Cabrera-Cabrera

Fluhrer

et al. 2020

Cell. Mol. Life Sci.

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Intramembrane proteolysis describes the cleavage of substrate proteins within their hydrophobic transmembrane segments. Several families of intramembrane proteases have been identified including the aspartyl proteases Signal peptide peptidase (SPP) and its homologues, the SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3. As presenilin homologues, they employ a similar catalytic mechanism as the well-studied γ-secretase. However, SPP/SPPL proteases cleave transmembrane proteins with a type II topology. The characterisation of SPP/SPPL-deficient mouse models has highlighted a still growing spectrum of biological functions and also promoted the substrate discovery of these proteases. In this review, we will summarise the current hypotheses how phenotypes of these mouse models are linked to the molecular function of the enzymes. At the cellular level, SPP/SPPL-mediated cleavage events rather provide specific regulatory switches than unspecific bulk proteolysis. By this means, a plethora of different cell biological pathways is influenced including signal transduction, membrane trafficking and protein glycosylation.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis

et al. 2020

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Ankylosing spondylitis (AS) is associated with autoantibody production to class II MHC‐associated invariant chain peptide, CD74/CLIP. In this study, we considered that anti‐CD74/CLIP autoantibodies present in sera from AS might recognize CD74 degradation products that accumulate upon deficiency of the enzyme signal peptide peptidase‐like 2A (SPPL2a). We analyzed monocytes from healthy controls ( n = 42), psoriatic arthritis ( n = 25), rheumatoid arthritis ( n = 16), and AS patients ( n = 15) for SPPL2a enzyme activity and complemented the experiments using SPPL2a‐sufficient and ‐deficient THP‐1 cells. We found defects in SPPL2a function and CD74 processing in a subset of AS patients, which culminated in CD74 and HLA class II display at the cell surface. These findings were verified in SPPL2a‐deficient THP‐1 cells, which showed expedited expression of MHC class II, total CD74 and CD74 N‐terminal degradation products at the plasma membrane upon receipt of an inflammatory trigger. Furthermore, we observed that IgG anti‐CD74/CLIP autoantibodies recognize CD74 N‐terminal degradation products that accumulate upon SPPL2a defect. In conclusion, reduced activity of SPPL2a protease in monocytes from AS predisposes to endosomal accumulation of CD74 and CD74 N‐terminal fragments, which, upon IFN‐γ‐exposure, is deposited at the plasma membrane and can be recognized by anti‐CD74/CLIP autoantibodies.

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Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors

Cited by 10 publications

References 25 publications

Catalyst Free, Nitromethane Assisted Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines

Catalyst Free, Nitromethane Assisted Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines

Physiological functions of SPP/SPPL intramembrane proteases

Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis

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