Expansion of the Structure-Activity Relationship Profile of Triaminopyrimidines as Inhibitors of Caspase-1.

ABSTRACT: Caspase-1 is a sought-after therapeutic target for inflammatory conditions due to its role in activation and release of pro-inflammatory cytokines, but there has been little success getting drugs into the clinic. We have previously shown triaminopyrimidines such as CK-1-41 are potent, reversible small molecule inhibitors of caspase-1, likely binding in an allosteric site within the enzyme. A series of analogs of CK-1-41 were synthesized and tested against caspase-1 to develop a more robust structure-activity relationship profile. In general, alkyl and aryl groups were well tolerated via an ethylene or methylene linkage to the piperazine nitrogen, with IC₅₀ values ranging from 13 to 200 nM. The most potent compounds were methylene linked o-tolyl (AE-2-21) and ethylene linked 4-tr

SUBMITTER: East A 

PROVIDER: S-EPMC11649019 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature