Laurent Knerr, Thomas Cogswell, Marie. Ahlqvist, Richard James Lewis, Anneli Nordqvist, Christian Sköld
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The Effect of gem-Difluorination on the Conformation and Properties of a Model Macrocyclic System
Conformational control of drug candidates to engineer improved potency and ADME properties is an ongoing area of research. Macrocyclic rings tend to offer a greater degree of rigidity than non-cyclised small molecules, and, as a result they are perfect platforms to instil conformational controls. In this study, the difluoroalkoxyphenyl moiety is examined as a tool to alter the conformation of macrocycles. A fluorinated and non-fluorinated macrocyclic matched pair is compared in terms of conformation preferences and related ADME properties. The synthesised macrocycles are found to give similar major conformations exhibiting a trans amide in the macrocyclic backbone. However, for the fluorinated macrocycle, the major trans amide conformation is in equilibrium with a cis amide minor conformation, seen by 1H NMR in a 4:1 ratio of trans/cis. The conformational fits for the minor fluorinated isomer demonstrate the out of plane preference of the difluoroalkoxy system encouraging the amide within the macrocycle backbone to adopt a cis conformation. A dramatic reduction in metabolic stability was found for the fluorinated macrocycle compared to the non-fluorinated and is postulated to be a result of the interconversion of trans amide to the cis amide, which may be more readily metabolised.
期刊介绍:
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.