Robinson, E; (2015) Development of Novel Metabolically Stable Analogues of PAR-1 Antagonist RWJ-58259. Doctoral thesis , UCL (University College London).

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Abstract

This thesis describes the investigation into the development of novel antagonists of the major thrombin receptor, protease-activated receptor-1, in the aim of generating analogues of the project lead compound with improved metabolic stability. Chapter 1 provides an introduction to the research project and the biological rationale for targeting protease-activated receptor-1 for inhibition. Chapter 2 describes modifications made to the synthetic route to produce RWJ-58259, the project lead, and subsequent biological evaluation carried out in order to confirm the compound’s identity and verify batch quality. Chapter 3 describes the investigation into the metabolic profile of RWJ 58259 to identify major sites of metabolism. Presented in this chapter are details of the syntheses of analogues of RWJ-58259 incorporating substituents designed to block possible sites of metabolism in the aim of improving in vivo stability. The development of an in vitro assay suited to screen analogues efficiently is described and the results from the biological evaluation of compounds synthesised are presented with discussion of the data generated.

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