From Merck's CCK- Antagonists Via 4-Amino-2(5H)- Furanones towards 5-Hydroxy-Pyrrol-2-Ones: Design, Synthesis and Evaluation of PNB-001 & PNB-081 as Experimental Therapeutic Agents in Pain Management

Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from muco-chloric acid and were optimised as CCK 1 / CCK 2 selective ligands using radio labelled binding assays. A potent CCK 1 selective ligand was identified (PNB-081: CCK1=20nM) as well as a potent CCK 2 ligand (PNB-001, IC50= 22nM) during a systematic SAR optimisation. The antagonism was confirmed for both ligands by using isolated tissue preparations with CCK 5 and CCK8S. Subsequent in vivo evaluation revealed analgesic activity for the gastrin CCK 2 antagonist PNB-001, in the hotplate and tail immersion test at 0.5mg /kg by IP administration in mice. The cholecystokinin antagonist PNB-081 potentiated the analgesic effect of morphine and reversed opiate tolerance in mice from doses >1 mg/kg by oral administration.