Goebel Matthias, Clemenz Markus, Staels Bart, Unger Thomas, Kintscher Ulrich, Gust Ronald
Institute of Pharmacy, Freie Universität of Berlin, Koenigin-Luise Strasse 2+4, 14195 Berlin, Germany.
ChemMedChem. 2009 Mar;4(3):445-56. doi: 10.1002/cmdc.200800285.
In addition to a proven efficacy in lowering blood pressure, the AT1 receptor blocker telmisartan has recently been shown to exert pleiotropic effects as a partial agonist of the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Based on these findings and an excellent side-effect profile, telmisartan may serve as a lead structure for the development of new PPARgamma ligands. Therefore, we analyzed the structural components of telmisartan to identify those necessary for PPARgamma activation. Synthesized compounds were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV. The data obtained in this structure-activity relationship (SAR) study provide the basis for the development of new PPARgamma ligands, which could lead to active compounds with a distinct, beneficial pharmacological profile compared with the existing full agonists. The basic 1-(biphenyl-4-ylmethyl)-1H-benzimidazole scaffold of telmisartan was identified as an essential moiety with either a carboxylic acid or tetrazole group at the C-2 position of the biphenyl. For maximum potency and activity, the alkyl chain in position 2 requires a minimum length of at least two C atoms (ethyl group), while the methyl group at position 4 of the benzimidazole core seems to contribute to partial activity. An additional benzimidazole at position 6 appears to be a further determinant of potency. Similar conclusions can be drawn for the methyl group in position 1.
除了在降低血压方面已证实的疗效外，血管紧张素Ⅱ 1型受体（AT1）阻滞剂替米沙坦最近还被证明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性作用。基于这些发现以及出色的副作用谱，替米沙坦可能成为开发新型PPARγ配体的先导结构。因此，我们分析了替米沙坦的结构成分，以确定激活PPARγ所需的成分。合成的化合物在使用3T3-L1前脂肪细胞的分化试验以及用pGal4-hPPARγDEF、pGal5-TK-pGL3和pRL-CMV瞬时转染的COS-7细胞的荧光素酶试验中进行测试。在该构效关系（SAR）研究中获得的数据为开发新型PPARγ配体提供了基础，这可能会产生与现有的完全激动剂相比具有独特有益药理学特征的活性化合物。替米沙坦的基本1-（联苯-4-基甲基）-1H-苯并咪唑支架被确定为一个必需部分，在联苯的C-2位置带有羧酸或四唑基团。为了达到最大效力和活性，2位的烷基链至少需要两个碳原子的最小长度（乙基），而苯并咪唑核心4位的甲基似乎有助于部分活性。苯并咪唑6位的一个额外苯并咪唑似乎是效力的另一个决定因素。对于苯并咪唑1位的甲基也可得出类似结论。
