Design, Synthesis, and Docking Studies of Novel Benzimidazoles for the Treatment of Metabolic Syndrome

作者：Mizuno Cassia S; Chittiboyina Amar G^*; Shah Falgun H; Patny Akshay; Kurtz Theodore W; Pershadsingh Harrihar A; Speth Robert C; Karamyan Vardan T; Carvalho Paulo B; Avery Mitchell A

来源：Journal of Medicinal Chemistry, 2010, 53(3): 1076-1085.

DOI：10.1021/jm901272d

In addition to lowering blood pressure, telmisartan, an angiotensin (AT,) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPAR gamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPAR gamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT, receptor with a K(i) = 13.4 nM, but it was devoid of PPAR gamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPAR gamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPAR gamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 mu M).

• 出版日期2010-2-11