Design, Synthesis, and Evaluation of Substituted Phenylpropanoic Acid Derivatives as Human Peroxisome Proliferator Activated Receptor Activators. Discovery of Potent and Human Peroxisome Proliferator Activated Receptor α Subtype-Selective Activators
Design, Synthesis, and Evaluation of Substituted Phenylpropanoic Acid Derivatives as Human Peroxisome Proliferator Activated Receptor Activators. Discovery of Potent and Human Peroxisome Proliferator Activated Receptor α Subtype-Selective Activators
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作为人类过氧化物酶体增殖物激活受体激活剂的取代苯丙酸衍生物的设计、合成和评估，发现有效的人类过氧化物酶体增殖物激活受体 α 亚型选择性激活剂。
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发表时间：
2003
期刊：
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通讯作者：
H. Miyachi
中科院分区：
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作者：
M. Nomura;T. Tanase;T. Ide;M. Tsunoda;Masahiro Suzuki;H. Uchiki;and Koji Murakami;H. Miyachi
制备取代的苯丙酸衍生物，作为亚型选择性人过氧化物酶体增殖物激活受体α（PPARα）激活剂研究的一部分。构效关系研究表明，含羧基的头部α位取代基的性质和立体化学、羧基与中心苯环的距离、中心苯环与远端苯环的连接基团、和分子远端疏水尾部的取代基都在决定PPAR亚型反式激活的效力和选择性方面起关键作用。本研究鉴定了有效的和人的PPARα选择性光学活性的α-烷基苯基丙酸衍生物，这将不仅是有用的药理学工具，以研究的生理和病理生理学的PPARα，而且作为候选药物用于治疗改变的代谢稳态，如血脂异常，肥胖症和糖尿病。
Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor α (PPARα) activators. Structure−activity relationship studies indicated that the nature and the stereochemistry of the substituent at the α-position of the head part containing the carboxyl group, the distance between the carboxyl group and the central benzene ring, the linking group between the central benzene ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the molecule all play key roles in determining the potency and selectivity of PPAR subtype transactivation. This study has led to the identification of potent and human PPARα selective optically active α-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARα but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesi...