Synthesis and Evaluation of Furan-2(5H)- One Based CCK Antagonists

Abstract

The furan based template, furan-2(5H)-one, is a relatively well known and important structure in nature. The structural arrangement of this template allows it to be susceptible to nucleophilic attack at different sites of this molecule, which can help in the formation of a new lead structure. This thesis had been compiled to document synthesis and evaluation of different classes of compound in the hope of finding new furanone based CCK antagonists.

Initially a new nociceptic assay involving tramadol potentiation, was developed using two CCK active pyrazolones which have previously been shown to possess CCK antagonist properties from in vitro receptor binding assays. Here these compounds have revealed significant tramadol potentiation in an in vivo ‘tail flick’ pain assay. The results have also shown a direct correlation between the receptor binding and the tramadol potentiation for these pyrazolones. This new assay was used in relation to newly synthesised compounds, in order to identify CCK active agents.

A range of 4-amino-5-alkoxy-furan-2(5H)-ones were formed via 5-alkoxy-furan-2(5H)-one building blocks based on a previously known lead structure, and were biologically evaluated using the fore-mentioned pain assay. Selected CCK antagonists showing good tramadol potentiation were submitted for other pharmacological tests. These indicated that compounds in this class possessed anxiolytic and / or antidepressant properties.Pyrrol-2,5-diones, formed as a by-product, during the synthesis of an anti-cancer agent, were developed and synthesised as the main product during this reaction. These compounds were also synthesised using an alternative route, which proceeded via the same mechanistic pathway, using the above mentioned 5-alkoxy-furan-2(5H)-ones. A further development of this pyrrole scaffold lead to the formation of a new class of 5-hydroxy-5-phenyl-pyrrol-2-ones. CCK antagonists were identified using the potentiation pain assay. Some of these compounds showed antidepressant and anxiolytic properties.

A novel class of but-2-enoic acid amides were designed and developed via molecular modelling studies using Merck’s L-365,260 antagonist as a comparison. Selected compounds were identified, via the nociceptic assay developed here and showed results comparable to existing standard CCK active pyrazolones CCK activity. These nonchiral CCK antagonist amides could possess anti-cancer properties as they contain a dichlorinated vinylic unit, which could help mimic the anti-cancer agent cisplatin. The furan-2(5H)-one building block used here has been shown to be a very important and exciting template which has yielded 3 different classes of compounds, each of which contained potent CCK antagonists.

Date of Award	2007
Original language	English
Awarding Institution	Aston University