Year 2

We have been successful with a cardiovascular drug re-purposing. The parent drug possesses significant adverse off-target properties and pharmacological liabilities. We have synthesized new drug candidates that showed improved potency compared to the parent drug molecule. The new compounds showed greater than 50-100-fold improvement in the on-target versus off-target effects compared to the currently used drug treatment. We have found that minor chemical changes to the position of key substituents on the molecule had a great impact on potency and off-target effects. This improvement in potency for the on-target effects of the molecule may lead to lower doses and/or greater therapeutic efficacy of the new drug candidate compared to the currently used drug.

We have nominated a small subset as lead compounds and advanced these compounds into pre-clinical testing that included chemical and metabolic stability studies. The results from chemical stability studies showed the lead drug candidates to be stable with a half-life of degradation of greater than 30 days. We have tested one of the lead compounds in liver microsomes to monitor potential hepatic metabolism of the compound. In addition, we studied the lead compounds in an in vitro measure of cytotoxicity and found the compounds are sufficiently non-toxic to move forward. The results showed one lead compound to have sufficient stability against metabolic enzymes of the liver to move the molecule forward into more advanced in vivo pre-clinical studies, including safety studies and efficacy studies.