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Issue 3, 2017
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Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

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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.

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

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Publication details

The article was received on 21 Dec 2016, accepted on 15 Feb 2017 and first published on 17 Feb 2017


Article type: Research Article
DOI: 10.1039/C6MD00707D
Citation: Med. Chem. Commun., 2017,8, 680-685
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    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 and P. Lattmann, Med. Chem. Commun., 2017, 8, 680
    DOI: 10.1039/C6MD00707D

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