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.