Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Bioorg Med Chem Lett. 2011 May 1;21(9):2736-9. doi: 10.1016/j.bmcl.2010.11.091. Epub 2010 Nov 25.
Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact with the receptor, which constituted the basis for the current study. We synthesized a novel series of substituted propenoic acids, such as fumaric acid esters, fumaric acid amides and cinnamic acid derivatives, and determined their affinities for the HCA2 receptor. We observed a rather restricted binding pocket on the receptor with trans-cinnamic acid being the largest planar ligand in our series with appreciable affinity for the receptor. Molecular modeling and analysis of the structure-activity relationships in the series suggest a planar trans-propenoic acid pharmacophore with a maximum length of 8 Å and out-of-plane orientation of the larger substituents.
烟酸（烟酰胺）作为一种抗血脂药物已在临床上使用了几十年。其主要作用靶点是羟基羧酸受体 HCA2（GPR109A），一种 G 蛋白偶联受体。其它酸和酸酯，如富马酸甲酯，也与该受体相互作用，这也是本研究的基础。我们合成了一系列新型取代的丙烯酸，如富马酸酯、富马酸酰胺和肉桂酸衍生物，并测定了它们与 HCA2 受体的亲和力。我们观察到受体上的结合口袋相当受限，反式肉桂酸是我们系列中最大的平面配体，对受体具有相当的亲和力。该系列的结构-活性关系的分子建模和分析表明，平面反式丙烯酸药效团的最大长度为 8 Å，较大取代基的取向为非共面。
