Isoxazolyl-serine-based agonists of peroxisome proliferator-activated receptor: design, synthesis, and effects on cardiomyocyte differentiation.
Isoxazolyl-serine-based agonists of peroxisome proliferator-activated receptor: design, synthesis, and effects on cardiomyocyte differentiation.
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DOI：
10.1021/ja046386l
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发表时间：
2004-12
影响因子：
15
通讯作者：
Zhi-Liang Wei;P. Petukhov;Fero Bizik;Joaquim Cabral Teixeira;M. Mercola;E. A. Volpe;R. Glazer;T. Willson;A. Kozikowski
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文献类型：
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作者：
Zhi-Liang Wei;P. Petukhov;Fero Bizik;Joaquim Cabral Teixeira;M. Mercola;E. A. Volpe;R. Glazer;T. Willson;A. Kozikowski
过氧化体增殖物激活受体(PPAR)是开发治疗人类代谢性疾病、炎症和癌症药物的重要分子靶点。已知它们可被各种结构不同的化合物激活。采用基于结构的药物设计方法，设计合成了一系列具有中等亲和力的新型异恶唑丝氨酸基PPAR配体。一些新的PPAR配体能够刺激小鼠ES细胞向心肌细胞分化。配基1a在第2-6天的1.25-20微米的浓度范围内测试是最活跃的，这与中胚层细胞可以被招募成为心肌细胞的时期相吻合。值得注意的是，已知的PPARα、伽马和Delta激动剂，例如非诺贝特、罗格列酮和GW501516，在本试验中都是无效的。
The peroxisome proliferator-activated receptors (PPARs) are important molecular targets for the development of drugs for the treatment of human metabolic diseases, inflammation, and cancer. They are known to be activated by a variety of structurally diverse compounds. Using a structure-based drug design approach, we designed and synthesized a series of novel isoxazolyl-serine-based PPAR ligands possessing moderate affinities. Some of the new PPAR ligands were able to stimulate cardiomyocyte differentiation from murine ES cells. Ligand 1a was the most active one tested at concentrations between 1.25 to 20 muM between days 2-6, coinciding with the period when mesodermal cells can be recruited to become cardiomyocytes. Notably, the known PPARalpha, gamma, and delta agonists tested, e.g., fenofibrate, rosiglitazone, and GW501516, were inactive in this assay.