Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel diseaseThe authors declare no competing interests.Electronic supplementary information (ESI) available. See DOI: 10.1039/c6md00707d

• Main Authors: Lattmann, E, Sattayasai, J, Narayanan, R, Ngoc, N, Burrell, D, Balaram, P. N, Palizdar, T, Lattmann, P
• Format: Journal Article
• Language: English
• Published: 23.03.2017
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c6md00707d

Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK 2 -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 IC 50 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 CCK 2 -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. Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK 2 -selective ligands using a range of assays.