Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
Med. Chem. Commun., 2017, Advance Article
DOI: 10.1039/C6MD00707D, Research Article
E. Lattmann, J. Sattayasai, R. Narayanan, N. Ngoc, D. Burrell, P. N. Balaram, T. Palizdar, P. Lattmann
Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using a range of assays.
Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
aSchool of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
E-mail: e.lattmann@aston.ac.uk
bDepartment of Pharmacology, Faculty of Medicine, Khon Kaen University, 40002 Khon Kaen, Thailand
cDepartment of Medicine, University of Tennessee Health Science Center, Memphis, USA
dPNB Vesper Life Science PVT, Cochin, India
Med. Chem. Commun., 2017, Advance Article
DOI: 10.1039/C6MD00707D
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.
General Method: The relevant amine (2.5 times excess) was added to a solution of lactone A – E (0.7 mol) in ether (10 ml) and stirred on ice for 30 minutes, allowing to warm up to RT over the time. The resultant mixture was poured into 5 ml water and separated by separating funnel. The mixture was washed with water three times. The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. All compounds gave an oily solid which were passed through a column (80% ether, 20% petrol ether). The resulting fractions were dried from excess solvent under vacuum to yield crystals. 4-Chloro-1-cyclopropyl-5-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one 1 Yield = 83 %; mp: 177-179 oC;
MS (APCI(+)): 193/195 (M+1), 250/252 (M+) m/z
1H NMR (CDCl3) 250 MHz: = 7.41 (m, 5H), 6.09 (s, 1H), 3.50 (m, 1H), 2.18 (m, 1H), 0.95-1.04 & 0.38-0.69 (m, 4H);
13C NMR (CDCl3) 167.4, 154.8, 135.2, 129.2, 128.8, 126.1, 122.2, 93.5, 22.6 , 3.8, 5.1;
IR (KBr-disc) max: 3416, 3260, 3105, 3011, 2363, 2338, 1671, 1602, 1490, 1450, 1409, 1369, 1256, 1144, 1032, 939, 833, 752, 702 cm-1 .
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