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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Importance of 5/6-aryl substitution on the pharmacological profile of 4 '-((2-propy-1H-benzo[d]imidazol-1-yl)methyl)-[1,1 '-bipheny1]-2-carboxylic acid derived PPAR gamma agonists
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Importance of 5/6-aryl substitution on the pharmacological profile of 4 '-((2-propy-1H-benzo[d]imidazol-1-yl)methyl)-[1,1 '-bipheny1]-2-carboxylic acid derived PPAR gamma agonists

机译：5/6-芳基取代在4' - （（2-propy-1h-苯并[d]咪唑-1-基）甲基） - [1,1'-biphy1] -2-羧酸的药物曲线上的重要性 衍生的PPAR伽玛激动剂

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摘要

In this structure-activity relationship study, the influence of aryl substituents at position 5 or 6 on the pharmacological profile of the partial PPAR gamma agonist 4'((2-propyl-1H-benzo[di]imidazol-1-yl)methyl)[1,1'-bipheny1]-2-carboxylic acid was investigated. This lead was previously identified as the essential part of telmisartan to induce PPAR gamma activation. Para-OCH3-phenyl substitution strongly increased potency and efficacy independent of the position. Both compounds represent full agonists because of strong hydrophobic contacts with the amino acid Phe363 in the ligand binding domain. Partial agonists with higher potency than telmisartan or the lead were obtained with OH or Cl substituents at the phenyl ring. Molecular modeling suggested additional hydrogen or halogen bonds with Phe360 located at helix 7. It is assumed that these interactions fix helix 7, thereby promoting a partial agonist conformation of the receptor. The theoretical considerations correlate very well with the results from the luciferase trans activation assay using hPPAR gamma-LBD as well as those from a time-resolved fluorescent resonance energy transfer(TR-FRET) assay in which the coactivator(TRAP220, PGC-1 alpha) recruitment and corepressor (NCoR1) release pattern was investigated. (C) 2016 Elsevier Masson SAS. All rights reserved.
机译：在该结构 - 活性关系研究中，芳基取代基在部分PPARγ激动剂4'的药理学分布上的影响（2-丙基-1H-苯并[二咪唑-1-基）甲基）研究了[1,1'-Bipheny1] -2-羧酸。此铅以前被鉴定为噻吩的基本部分，以诱导PPARγ激活。 Para-Och3-苯基取代强烈增加效力和效力与该位置无关。由于与配体结合结构域中的氨基酸PHE363强的疏水触点，两种化合物都代表完全激动剂。在苯环的OH或Cl取代基获得具有比Telmisartan更高的效力更高的效力或铅的部分激动剂。分子建模建议额外的氢或卤素键与位于螺旋7的PHE360。假设这些相互作用固定螺旋7，从而促进受体的部分激动剂构象。通过使用HPPARγ-LBD的荧光素酶反应激活测定结果以及来自调节剂（TRAP220，PGC-1α的TR-FRET）测定的荧光素酶反应激活测定的结果非常好，从荧光素酶反式激活测定结果中的结果非常好。 ）调查招聘和内核压力（Ncor1）释放模式。 （c）2016年Elsevier Masson SAS。版权所有。

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