Opening NADPH oxidase inhibitors for in vivo translation

Triazolopyrimidine derivatives from the VAS library have been found to be efficient and selective NADPH oxidase (NOX) inhibitors in vitro. In spite of numerous publications on this compound class detailing efficacy for the treatment of cardiovascular diseases, in vivo translation is challenged by their very low water solubility which is preventing further use of these compounds and blocking clinical translation. Therefore, we addressed the challenge of water solubility for three triazolopyrimidine derivatives, VAS2870, VAS3947, and VAS4024, and developed formulations for oral or parenteral application with translational potential into preclinical and clinical studies. Based on its physico-chemical properties, VAS3947 was selected and formulated by spray drying, microemulsification, and complexation with different cyclodextrin (CD) derivatives. The poor water solubility of VAS3947 was successfully increased in all approaches. The supersaturation ratio for seven spray dried formulations and four microemulsions ranged from 3-9 and 8 to 19 after 120min, respectively. For six CDs a supersaturation ratio was observed between 3 and 174 after 20h, with an inclusion of the compound within the CD's cavity as well as interaction with its outside. In conclusion, we successfully developed formulations opening this promising compound class for oral or parenteral in vivo administration.