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

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.