Development of AQP9 inhibitors for improved treatment of diabetes and prevention of comorbidities

Purpose and goal

The aim of this project was to confirm the therapeutic potential of newly established aquaporin 9 inhibitors for the treatment of sepsis, as well as to advance the pharmaceutical development work from prototype to a lead candidate molecule, and to prepare the project for further toxicological characterization before the first clinical trials. Through this work, the project is transferred from TLR3 to TLR4.

Expected results and effects

A series of experiments (in vitro and in vivo) have shown a clear anti-inflammatory, organ-protecting effect of a prototype AQP9 inhibitor, in a model of sepsis in mouse. A series of molecules with improved pharmacokinetic properties and with retained organ-protective effect were developed during the project. A lead molecule has been chosen for further development work, and synthetic routes suitable for scaling up production have been established.

Planned approach and implementation

Protection against damage by bacterial sepsis by blocking AQP9 could be demonstrated in a mouse model. Damage to the heart, kidneys and liver was largely reversed by AQP9 inhibition. Reduction of the underlying inflammation was identified as the mechanism of the observed effect. Pharmacological improvement of our molecules was led by previously established structure-activity data.