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The Development of Novel Vorapaxar Analogues as Topical Protease Activated Receptor-1 Antagonists for the Treatment of Idiopathic Pulmonary Fibrosis

Knight, EF; (2016) The Development of Novel Vorapaxar Analogues as Topical Protease Activated Receptor-1 Antagonists for the Treatment of Idiopathic Pulmonary Fibrosis. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The overall aim of this project was to design and synthesise novel Protease Activated Receptor-1 (PAR-1) inhibitors in order to develop a novel treatment for Idiopathic Pulmonary Fibrosis (IPF). After finding the commercially available, allosteric PAR-1 inhibitor, “Q94” inactive and insoluble, focus switched to making novel vorapaxar analogues. A newly published synthetic route towards himbacine was successfully adapted to give vorapaxar analogues with a C-9-keto group. These were shown to have moderate potency against PAR-1 in a FLIPR calcium flux assay. After further synthetic route optimisation and investigation another novel vorapaxar analogue was identified. Compound (-)-94 was shown to be the most potent of the series of compounds tested, achieving an IC50 of 27 nM. In the same assay vorapaxar gave an IC50 of 13 nM. This makes (-)-94 a novel, potent, PAR-1 inhibitor worthy of further investigation and development as a potential IPF drug.

Type: Thesis (Doctoral)
Title: The Development of Novel Vorapaxar Analogues as Topical Protease Activated Receptor-1 Antagonists for the Treatment of Idiopathic Pulmonary Fibrosis
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright material has been removed from ethesis.
Keywords: Idiopathic Pulmonary Fibrosis, IPF, Protease Activated Receptor-1, PAR-1, Vorapaxar
URI: http://discovery.ucl.ac.uk/id/eprint/1473879
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