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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

Journal: Scholarena Journal of Pharmacy and Pharmacology (Vol.5, No. 1)

Publication Date:

Authors : ;

Page : 1-12

Keywords : Phenyl-Pyrrolone; CCK antagonist; Cholecystokinin; Gastrin; Analgesic;

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Abstract

Study aim: To prepare and evaluate CCK gastrin antagonists from readily available materials such as furfural and to focus on inflammatory pain management. SAJ Pharmacy and Pharmacology 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 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.

Last modified: 2018-11-29 19:13:28