Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

  • Medchemcomm. 2017 Feb 17;8(3):680-685. doi: 10.1039/c6md00707d.
E Lattmann  1 ,  J Sattayasai  2 ,  R Narayanan  3 ,  N Ngoc  1 ,  D Burrell  1 ,  P N Balaram  4 ,  T Palizdar  1 ,  P Lattmann  4
Affiliations
  • 1. School of Life and Health Sciences , Aston University , Aston Triangle , Birmingham B4 7ET , England , UK . Email: [email protected].
  • 2. Department of Pharmacology , Faculty of Medicine , Khon Kaen University , 40002 Khon Kaen , Thailand.
  • 3. Department of Medicine , University of Tennessee Health Science Center , Memphis , TN , USA.
  • 4. PNB Vesper Life Science PVT , Cochin , Kerala , India.
PMID: 30108786 DOI: 10.1039/c6md00707d
Abstract

Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as a standard. The IC50 of PNB-001 was determined to be 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg-1 PNB-001 was equivalent to 40 mg kg-1 tramadol. The CCK2-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg-1 dose of prednisolone, which served as a standard.

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