当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists.

Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists.

Abstract：

:In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Rikimaru K,Wakabayashi T,Abe H,Tawaraishi T,Imoto H,Yonemori J,Hirose H,Murase K,Matsuo T,Matsumoto M,Nomura C,Tsuge H,Arimura N,Kawakami K,Sakamoto J,Funami M,Mol CD,Snell GP,Bragstad KA,Sang BC,Dougan DR,Tanak

doi

10.1016/j.bmc.2012.03.036

subject

Has Abstract

pub_date

2012-05-15 00:00:00

pages

3332-58

issue

10

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(12)00226-X

journal_volume

20

pub_type

杂志文章

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