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

E. Lattmann*, J. Sattayasai, R. Narayanan, N. Ngoc, D. Burrell, P.N. Balaram, T. Palizdar, P. Lattmann

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)680-685
Number of pages6
JournalMedChemComm
Volume8
Issue number3
DOIs
Publication statusPublished - 17 Feb 2017

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    Lattmann, E., Sattayasai, J., Narayanan, R., Ngoc, N., Burrell, D., Balaram, P. N., Palizdar, T., & Lattmann, P. (2017). Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease. MedChemComm, 8(3), 680-685. https://doi.org/10.1039/c6md00707d