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.

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
College of Health & Life Sciences > School of Biosciences
Uncontrolled Keywords: Biochemistry,Pharmaceutical Science
Publication ISSN: 2040-2511
Last Modified: 20 May 2024 07:19
Date Deposited: 13 Apr 2017 11:05
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2017-02-17
Accepted Date: 2017-02-15
Submitted Date: 2016-12-21
Authors: Lattmann, E.
Sattayasai, J.
Narayanan, R.
Ngoc, N.
Burrell, D.
Balaram, P.N.
Palizdar, T.
Lattmann, P.



Version: Accepted Version

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