European journal of medicinal chemistry, 2022-02, Vol.229, p.114002-114002, Article 114002
2022
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- Autor(en) / Beteiligte
- Titel
- Design, synthesis and biological evaluation of 1,5-disubstituted α-amino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders
- Ist Teil von
- European journal of medicinal chemistry, 2022-02, Vol.229, p.114002-114002, Article 114002
- Ort / Verlag
- France: Elsevier Masson SAS
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1β release in activated macrophages in the low μM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19. [Display omitted] •Inhibitors of caspase-1 can modulate the inflammatory response.•New caspase-1 non-covalent inhibitors were designed by a substrate mimic approach.•1,5-disubstituted-α-amino-tetrazole derivatives were synthesized by 4-Ugi MCR.•Compound 16aa showed in vitro activity at low μM level.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0223-5234eISSN: 1768-3254DOI: 10.1016/j.ejmech.2021.114002Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8598261
- Format
- –
- Schlagworte
- 1,5-Disubstituted α-amino tetrazole derivatives, Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal - pharmacology, Anti-inflammatory drug candidates, Autoimmune Diseases - drug therapy, Caspase 1 - drug effects, Caspase-1 non-covalent inhibitors, Cell Division - drug effects, COVID-19, Drug Design, Drug Evaluation, Preclinical, Humans, Inflammasome, Inflammasomes - drug effects, Inflammation - drug therapy, Interleukin-1beta - metabolism, Macrophages - drug effects, Macrophages - metabolism, Multicomponent reactions, Serpins - chemical synthesis, Serpins - pharmacology, Tetrazoles - chemical synthesis, Tetrazoles - pharmacology, Tetrazoles - therapeutic use, U937 Cells, Viral Proteins - chemical synthesis, Viral Proteins - pharmacology