Designed Multitarget Ligands for Metabolic Diseases

The cardiometabolic syndrome (MetS) is a multifactorial disease cluster consisting of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus and obesity. Pharmacological intervention in the MetS is dependent on numerous drugs, thus polypharmacy is an obvious problem in the treatment of MetS patients. Our studies focus on the dual target approach to accomplish a more efficient therapy for MetS. The two targets addressed by dual ligand design are the soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). In vivo studies could demonstrate that even though an inhibitor of sEH (sEH-I) or PPARγ agonist (PPARγ-A) have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome. In a follow-up study, we designed lead-like merged N-benzyl benzamides which were able to modulate sEH and PPARγ. Structure activity relationship studies on both targets were performed resulting in an equipotent submicromolar (IC50 (sEH) = 0.3 µM/ EC50 (PPARγ) = 0.3 µM) propionic acid N-benzyl benzamide derivative RB394. Evaluation in vitro and in vivo displayed good ADME properties qualifying the novel dual modulator as pharmacological tool compound for long term animal models of MetS [1]. 8-week evaluation in spontaneously hypertensive obese rats (SHROB), a rat model of MetS, demonstrated excellent efficacy including simultaneous reduction of blood pressure, improvement of glucose tolerance, improvement of lipid and cholesterol levels, and organ protection. These results could be confirmed in an 8-week curative study in ZSF1 rat model of MetS [2]. Furthermore, we could show that in murine UUO model, RB394 treatment outperforms single target sEH-I and PPARγ-A as well as the combination of both.[3]. Finally, we could show that only one enantiomer of the racemic RB394 is the eutomer on both targets. We demonstrated its ability to to promote adipocyte browning and simultaneously exhibits cardioprotective activity.[4]