1080-P: Addressing the Safety Challenges of Aldose Reductase Inhibition: Development of AT-001 for Diabetic Cardiomyopathy, a Potent and Selective Next Generation Aldose Reductase Inhibitor

Diabetic Cardiomyopathy (DbCM) leading to overt heart failure is a common sequelae of both type 1 and type 2 diabetes. Prior attempts to develop treatments for DbCM via inhibition of Aldose Reductase (AR) were unsuccessful, due to low AR binding affinity and off-target binding with Aldehyde Reductase (AldR), an enzyme critical for detoxification of aldehydes in the liver and normal hepatocyte function. This resulted in liver-related safety and tolerability issues with first generation ARIs. We report on the selectivity and specificity of AT-001, a novel small molecule ARI with optimized affinity and specificity for AR and minimal to zero off-target AldR activity.

Methods and Results: AT-001 was evaluated for AR binding affinity vs. zopolrestat, a prior best in class ARI, which had been challenged with liver toxicity issues in clinical development. AT-001 demonstrated logarithmically improved AR inhibitory activity (IC₅₀ of 30 pmol for AT-001 and 10 nmol for zopolrestat). Liver enzyme evaluations demonstrated that AT-001 showed no inhibition of AldR at 50x and 100x EC₅₀ levels in assay medium, while zopolrestat inhibited AldR by 50% and 60% respectively (spec activity of 2.3 and 1.9 mmol NADPH/min/mg prot.). Additionally no elevations of ALT/AST’s were observed with AT-001 at doses up to 50x EC₅₀, in contrast to zopolrestat which showed dose dependent release of ALT and AST (consistent with hepatocyte damage and eventual cell death). Finally, AT-001 was evaluated in a standard off-target receptor binding analysis of 87 substrates (13 enzymes, 74 binding assays); with no significant results (>50% inhibitory activity) observed.

Conclusion: The unique structure and activity of AT-001 provide potent selectivity for Aldose Reductase and lack of off-target effects. The in-vitro safety of this agent together with the positive safety data from the phase 1/2 program, supports the ongoing pivotal study in DbCM.