US EPA

3491101 

Journal Article 

Variation of the aryl substituent on the piperazine ring within the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold unveils potent, non-competitive inhibitors of the inflammatory caspases 

Kent, CR; Bryja, M; Gustafson, HA; Kawarski, MY; Lenti, G; Pierce, EN; Knopp, RC; Ceja, V; Pati, B; Walters, DE; Karver, CE 

2016 

Yes 

Bioorganic & Medicinal Chemistry Letters
ISSN: 0960-894X
EISSN: 1464-3405 

26 

22 

5476-5480 

English 

27777011 

10.1016/j.bmcl.2016.10.025 

WOS:000388251400018 

https://www.scopus.com/inward/record.uri?eid=2-s2.0-84994048522&doi=10.1016%2fj.bmcl.2016.10.025&partnerID=40&md5=09509c5051f4541bddf310eec8ff3d6d
Exit
 

The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1-41 displaying low nanomolar Ki values across this family of caspases. Three analogs were nearly 10 fold selective for caspase-5 over caspase-1 and -4. The compounds display non-competitive, time dependent inhibition profiles. To our knowledge, this series is the first example of small molecule inhibitors of all three inflammatory caspases.