Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
J Med Chem. 2010 Feb 11;53(3):1076-85. doi: 10.1021/jm901272d.
In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) 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(1) 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 PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 microM).
除了降低血压，血管紧张素 II 受体阻断剂替米沙坦，最近还被证明具有作为核过氧化物酶体增殖物激活受体 γ（PPARγ）部分激动剂的多效作用。基于这些发现和替米沙坦与罗格列酮在 PPARγ活性位点的对接构象相似，设计并合成了两类苯并咪唑衍生物作为双重 PPARγ激动剂/血管紧张素 II 拮抗剂，用于治疗代谢综合征。双苯并咪唑衍生物 4 对 AT（1）受体具有最佳亲和力，K（i）= 13.4 nM，但没有 PPARγ活性。另一方面，单苯并咪唑衍生物 9 在 PPARγ转录激活测定中显示出最高的活性（69%激活），对 AT（1）受体没有亲和力。对接研究导致了具有双重活性的分子 10 的设计，其对 PPARγ具有中等活性（29%），对 AT（1）受体具有亲和力（K（i）= 2.5 microM）。
