Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome

Article abstract of DOI:10.1021/jm901272d

In addition to lowering blood pressure, telmisartan, an angiotensin (AT₁) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor γ (PPARγ). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPARγ active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPARγ agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT₁ receptor with a K_i=13.4 nM, but it was devoid of PPARγ activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPARγ transactivation assay (69% activation) with no affinity for the AT₁ receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARγ activity (29%) and affinity for the AT₁ receptor (K_i=2.5 μM).