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A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by x-ray analysis. Using a radiolabelled binding assay, potent CCK1 selective ligands were identified (CCK1: 12nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed insurmountable CCK antagonistic properties. Using electrically induced contractions and CCK induced contractions on isolated rat tissues, an irreversible antagonism was established. In vitro, using selected cancer cell lines, the viability was measured and IC-50 was obtained in the nanomolar range. Using allograft models the treatment regimen was further optimised leading to a 48h dosing interval. The downstream analysis revealed inhibition of proliferation analysed via the Ki 67 biomarker. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X=H and X=F a fluorinated analogue (PNB-028), showed a strong inhibition of tumour growth in a human pancreatic cell line (MIAPACA) at 50mg/kg by oral administration. PK was analysed and the overall conclusion was drawn. Figure 1: Drug design from natural product Asperlicin, towards fully synthetic Devazepide, a CCK1 selective antagonist. N NH

modern approaches in drug designing

Irreversible Cholecystokinin-1 Receptor Antagonists Pnb-028/81: N-Isobutyl-5-Hydroxy-5-Aryl-Pyrrol-2- Ones as Experimental Therapeutic Agents against Colon and Pancreatic Cancer