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

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2021 Nov 26

PMID 34823899

Citations 3

Authors

Fausta Ulgheri

Pietro Spanu

Francesco Deligia

Giovanni Loriga

Maria Pia Fuggetta

Iris de Haan

Ajay Chandgudge

Matthew Groves

Alexander Domling

Affiliations

Soon will be listed here.

Abstract

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.

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