title: 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.
abstract: 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 Kivalues 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.
authors: Department of Chemistry, DePaul University, 1110 W Belden Ave, Chicago, IL 60614, United States.
authors: Courtney R
authors: CR
authors: Kent
authors: Department of Chemistry, DePaul University, 1110 W Belden Ave, Chicago, IL 60614, United States.
authors: Magdalena
authors: M
authors: Bryja
authors: Department of Chemistry, DePaul University, 1110 W Belden Ave, Chicago, IL 60614, United States.
authors: Helen A
authors: HA
authors: Gustafson
authors: Department of Chemistry, DePaul University, 1110 W Belden Ave, Chicago, IL 60614, United States.
authors: Margaret Y
authors: MY
authors: Kawarski
authors: Department of Chemistry, DePaul University, 1110 W Belden Ave, Chicago, IL 60614, United States.
authors: Gena
authors: G
authors: Lenti
authors: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S Wood St, Chicago, IL 60612, United States.
authors: Emily N
authors: EN
authors: Pierce
authors: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S Wood St, Chicago, IL 60612, United States.
authors: Rachel C
authors: RC
authors: Knopp
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL 60064, United States.
authors: Victor
authors: V
authors: Ceja
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL 60064, United States.
authors: Bhabna
authors: B
authors: Pati
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL 60064, United States.
authors: D Eric
authors: DE
authors: Walters
authors: Department of Chemistry, DePaul University, 1110 W Belden Ave, Chicago, IL 60614, United States. Electronic address: ckarver@depaul.edu.
authors: Caitlin E
authors: CE
authors: Karver
mesh_terms: D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D053471:Caspases, Initiator / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D054852:Small Molecule Libraries; C093516:CASP4 protein, human; C099217:CASP5 protein, human; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: Caspase-1; Caspase-4; Caspase-5; Inflammasome; Inflammation