Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations.
Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations.
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DOI：
10.1021/jm8000778
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发表时间：
2008-05
影响因子：
7.3
通讯作者：
Yanan Zhang;Jason P. Burgess;M. Brackeen;A. Gilliam;S. Mascarella;Kevin M Page;H. Seltzman;B. F. Thomas
中科院分区：
文献类型：
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作者：
Yanan Zhang;Jason P. Burgess;M. Brackeen;A. Gilliam;S. Mascarella;Kevin M Page;H. Seltzman;B. F. Thomas
1(SR141716)的结构-活性关系(SARS)已经被广泛地记录下来，然而，这类化合物的构象性质却没有得到足够的关注。为了更好地了解受体识别的最佳配体构象，我们设计并合成了一些1的衍生物，包括一个四碳桥联的分子(11)，以限制二芳基环的旋转。对11的计算分析表明，两个芳基环的转动能垒约为20千卡/摩尔。核磁共振研究确定了该化合物的能垒约为18千卡/摩尔，并暗示可能存在阿托品。受体结合和功能研究表明，与1相比，这些化合物的亲和力和效力都有所降低。这表明，我们的结构修改要么将环系统限制在受体相互作用的次优取向上，要么引入空间位阻导致不利于与受体的空间相互作用，和/或分子静电势的相对温和变化导致不利的库仑相互作用。
Structure-activity relationships (SARs) of 1 (SR141716) have been extensively documented, however, the conformational properties of this class have received less attention. In an attempt to better understand ligand conformations optimal for receptor recognition, we have designed and synthesized a number of derivatives of 1, including a four-carbon-bridged molecule (11), to constrain rotation of the diaryl rings. Computational analysis of 11 indicates approximately 20 kcal/mol energy barrier for rotation of the two aryl rings. NMR studies have determined the energy barrier to be approximately 18 kcal/mol and suggested atropisomers could exist. Receptor binding and functional studies with these compounds displayed reduced affinity and potency when compared to 1. This indicates that our structural modifications either constrain the ring systems in a suboptimal orientation for receptor interaction or the introduction of steric bulk leads to disfavored steric interactions with the receptor, and/or the relatively modest alterations in the molecular electrostatic potentials results in disfavored Coulombic interactions.