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首页> 外文期刊>Journal of Medicinal Chemistry >Design, Synthesis, and Docking Studies of Novel Benzimidazoles for the Treatment of Metabolic Syndrome
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Design, Synthesis, and Docking Studies of Novel Benzimidazoles for the Treatment of Metabolic Syndrome

机译：新型苯并咪唑类药物治疗代谢综合征的设计，合成和对接研究

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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).
机译：除降低血压外，最近还显示替米沙坦是一种血管紧张素（AT）受体阻滞剂，可作为核过氧化物酶体增殖物激活受体γ（PPARγ）的部分激动剂发挥多效作用。基于这些发现以及替米沙坦和罗格列酮在PPARγ活性位点之间的对接姿势相似性，设计并合成了两类苯并咪唑衍生物作为PPARγ激动剂/血管紧张素II双重拮抗剂，可能用于治疗代谢综合征。化合物4（一种双苯并咪唑衍生物）对AT受体表现出最佳亲和力，K-1 = 13.4 nM，但没有PPARγ活性。另一方面，单苯并咪唑衍生物在PPARγ反式激活分析中显示最高活性（69％激活），而对AT（1）受体没有亲和力。对接研究导致设计出具有双重活性的分子10，具有中等的PPARγ活性（29％）和对AT（1）受体的亲和力（K-1 = 2.5μM）。

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