The design and synthesis of novel APIs based upon topiramate

Abstract

The research project, conducted in collaboration with Onyx Scientific Limited and Newcastle University, is focused on the anti-convulsant drug topiramate that is best known as a treatment for epilepsy. The established data on the efficacy and limitations of topiramate highlighted it as a promising drug candidate for reprofiling, repurposing or modification. The interest in topiramate stems primarily from its multi-factorial mode of biological action that results in a complex combination of pharmacological effects. This is manifested by the drug having a complex side effects profile with the most common being related to the central nervous system, weight loss and gastrointestinal disorders. The drug influences the activity of a number of in vivo sites including certain types of voltage activated sodium and calcium ion channels, AMPA glutamate receptors and particular isozymes of the enzyme carbonic anhydrase (CA). Of particular interest to this work is the specific inhibition of mitochondrial CAs, CAVA and CAVB by topiramate. The inhibition of these mitochondrial CAs is thought to contribute to the weight loss effects observed in patients being treated with topiramate. The project aims to develop novel selective CA inhibitors (CAIs) that have inhibitory properties towards only particular and relevant CAs. It is hoped that this will enable the pharmacological activity of topiramate to be optimised and certain of its aspects positively exploited whilst limiting toxicity and off-target biological effects. The objective of the project is to identify potential new APIs by assessing the biological activity of known derivatives of topiramate on the CA targets of interest and by creating novel molecules that introduce structural modifications to topiramate that may increase the specificity for certain CAs and vary the drug’s pharmacological effects. The approach of the project is to undertake a classical drug design cycle using modern drug discovery techniques. In silico models were used to identify compounds, both known and novel, which show promising interactions with one or more of the target active sites and which therefore may demonstrate a selective biological response. The in silico hits generated from modelling will be the primary synthetic targets and are the focus of this research.