Synthesis of novel and potent vorapaxar analogues

Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent -himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with th...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2016-01, Vol.14 (12), p.3264-3274
Main Authors: Knight, Emily, Robinson, Eifion, Smoktunowicz, Natalia, Chambers, Rachel C, Aliev, Abil E, Inglis, Graham G, Chudasama, Vijay, Caddick, Stephen
Format: Article
Language:English
Subjects:
Dose-Response Relationship, Drug
Fibroblasts - drug effects
Fibroblasts - metabolism
Humans
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacology
Lung - cytology
Molecular Structure
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Receptor, PAR-1 - antagonists & inhibitors
Receptor, PAR-1 - metabolism
Structure-Activity Relationship
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Summary:Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent -himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC 50 of 27 nM. Unlocking novel and potent vorapaxar analogues by functionalisation of previously unexplored positions on the parent vorapaxar scaffold.
ISSN:1477-0520
1477-0539
DOI:10.1039/c5ob02541a