CCK2–Gastrin Antagonist: Development of PNB-001 (4-Chloro- 5-Hydroxy-1-Phenylethyl-5-Phenyl-1, 5-Dihydro-Pyrrol-2-one) as Anti-Inflammatory Analgesic


Study aim: To prepare and evaluate CCK gastrin antagonists from readily available materials such as furfural and to focus on inflammatory pain management. Methods: Receptor binding assays, isolated tissue preparations and selected animal models were applied to evaluate the lead molecule PNB-001. Results: Arylated 5-hydroxy–pyrrol-2-ones were prepared in 3 synthetic steps from furfural and subsequently optimised as CCK2 selective ligands using radiolabelled binding assays. Originally a CCK1 selective lead structure was identified and from that lead, a potent and selective CCK2 ligand (PNB-001, IC50= 22 nM) was fully SAR optimised. The antagonism was confirmed for PNB-001 by using isolated tissue preparations with CCK5. Subsequent in vivo evaluation revealed analgesic activity for the gastrin CCK2 antagonist PNB-001, in the hotplate and tail immersion test at 0.5mg /kg by IP administration in mice. PNB-001 was superior in the formalin test to the morphine standard by oral administration and in the x-maze test the anxiolytic activity was greater in magnitude than diazepam. Conclusion: The front runner PNB-001 completed preclinical development and will enter clinical phase 1.

Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Life & Health Sciences > Cell & Tissue Biomedical Research
Additional Information: This is an open access publication, with no specified licence for re-use
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Related URLs: http://article. ... y-Analgesic.pdf (Publisher URL)
PURE Output Type: Article
Published Date: 2018-05-01
Published Online Date: 2018-05-01
Accepted Date: 2018-05-01
Authors: Lattmann, Eric
Sattayasai, Jintana
Narayanan, Ramesh
Benyamen, Julian
Balaram, Padinjarethalakal N.
Lattmann, Pornthip



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