Design, synthesis and in vitro evaluation of a series of a-substituted phenylpropanoic acid PPARy agonists to further investigate the stereochemistry-activity relationship
Design, synthesis and in vitro evaluation of a series of a-substituted phenylpropanoic acid PPARy agonists to further investigate the stereochemistry-activity relationship
复制标题
一系列α-取代苯丙酸PPARγ激动剂的设计、合成和体外评价，以进一步研究立体化学-活性关系
DOI：
10.1016/j.bmc.2012.08.061
复制
发表时间：
2012
期刊：
影响因子：
--
通讯作者：
et.al.
中科院分区：
文献类型：
--
作者：
Masao Ohashi;et.al.
我们先前证明，α-苄基苯丙酸型PPARγ选择性激动剂6表现出相反的立体化学-活性关系，即与结构相似的α-乙基苯丙酸型PPAR激动剂相比，（R）-对映体是比（S）-对映体更有效的PPARγ激动剂。本文设计、合成并评价了光学活性的α-环己基甲基苯丙酸衍生物7和α-苯乙基苯丙酸衍生物8。有趣的是，α-环己基甲基衍生物显示出立体化学-活性关系的逆转[即，(R)比（S）更有效]，如α-苄基衍生物，而α-苯乙基衍生物显示“正常”关系[（S）比（R）更有效]。这些结果表明，在相对于羧基的β-位上存在支链碳原子是反向立体化学-活性关系的关键决定因素。
We previously demonstrated that the α-benzylphenylpropanoic acid-type PPARγ-selective agonist 6 exhibited a reversed stereochemistry–activity relationship, that is, the (R)-enantiomer is a more potent PPARγ agonist than the (S)-enantiomer, compared with structurally similar α-ethylphenylpropanoic acid-type PPAR agonists. Here, we designed, synthesized and evaluated the optically active α-cyclohexylmethylphenylpropanoic acid derivatives 7 and α-phenethylphenylpropanoic acid derivatives 8, respectively. Interestingly, α-cyclohexylmethyl derivatives showed reversal of the stereochemistry–activity relationship [i.e., (R) more potent than (S)], like α-benzyl derivatives, whereas α-phenethyl derivatives showed the ‘normal’ relationship [(S) more potent than (R)]. These results suggested that the presence of a branched carbon atom at the β-position with respect to the carboxyl group is a critical determinant of the reversed stereochemistry–activity relationship.