Substituted 2-[(4-Aminomethyl)phenoxy]-2-methylpropionic Acid PPAR Agonists. 1. Discovery of a Novel Series of Potent HDLc Raising A
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- 作者：Michael L. Sierra ; Vé ; ronique Beneton ; Anne-Bé ; né ; dict Boullay ; Thierry Boyer ; Andrew G. Brewster ; Fré ; dé ; ric Donche ; Marie-Claire Forest ; Marie-Hé ; lè ; ne Fouc
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：February 22, 2007
- 年：2007
- 卷：50
- 期：4
- 页码：685 - 695
- 全文大小：320K
- 年卷期：v.50,no.4(February 22, 2007)
- ISSN：1520-4804
文摘
The peroxisome proliferator activated receptors PPAR
hars/alpha.gif" BORDER=0>, PPARhars/gamma.gif" BORDER=0 >, and PPARhars/delta.gif" BORDER=0 > are ligand-activated transcriptionfactors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoproteincholesterol and lower levels of triglycerides in part through their activity as PPARhars/alpha.gif" BORDER=0> agonists; however, thelow potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable todevelop more potent and selective PPARhars/alpha.gif" BORDER=0> agonists. Modification of the selective PPARhars/delta.gif" BORDER=0 > agonist 1(GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a markedshift in potency and selectivity toward PPARhars/alpha.gif" BORDER=0> agonism. Optimization of the series gave 25a, which showsEC50 = 4 nM on PPARhars/alpha.gif" BORDER=0> and at least 500-fold selectivity versus PPARhars/delta.gif" BORDER=0 > and PPARhars/gamma.gif" BORDER=0 >. Compound 25a(GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
hars/alpha.gif" BORDER=0>, PPARhars/gamma.gif" BORDER=0 >, and PPARhars/delta.gif" BORDER=0 > are ligand-activated transcriptionfactors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoproteincholesterol and lower levels of triglycerides in part through their activity as PPARhars/alpha.gif" BORDER=0> agonists; however, thelow potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable todevelop more potent and selective PPARhars/alpha.gif" BORDER=0> agonists. Modification of the selective PPARhars/delta.gif" BORDER=0 > agonist 1(GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a markedshift in potency and selectivity toward PPARhars/alpha.gif" BORDER=0> agonism. Optimization of the series gave 25a, which showsEC50 = 4 nM on PPARhars/alpha.gif" BORDER=0> and at least 500-fold selectivity versus PPARhars/delta.gif" BORDER=0 > and PPARhars/gamma.gif" BORDER=0 >. Compound 25a(GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.