Analysis of the critical structural determinant(s) of species-selective peroxisome proliferator-activated receptor alpha (PPARα)-activation by phenylpropanoic acid-type PPARα agonists

被引：26

作者：

Miyachi, H ^{[1
]}

Uchiki, H ^{[1
]}

机构：

[1] Kyorin Pharmaceut Co Ltd, Discovery Res Labs, Shimotsuga, Tochigi 3290114, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 19期

关键词：

D O I：

10.1016/S0960-894X(03)00715-7

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In order to identify the critical structural feature(s) of phenylpropanoic acid-type PPARalpha agonists, such as KCL, which exhibit human peroxisome proliferator-activated receptor alpha (PPARalpha)-selective activation, transient transactivation assay of KCL and related derivatives was performed with PPARalpha containing wild-type and point-mutated (1272F or T279M) ligand-binding domain. The results indicated that the interaction of the distal hydrophobic tail part of KCL and related derivatives with amino acid residue 272 (isoleucine) in the helix three region of PPARalpha is of primary importance for human-selective PPARalpha activation. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：3145 / 3149

页数：5

共 16 条

[1] A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPARα agonist with potent lipid-lowering activity [J].

Brown, PJ ;

Winegar, DA ;

Plunket, KD ;

Moore, LB ;

Lewis, MC ;

Wilson, JG ;

Sundseth, SS ;

Koble, CS ;

Wu, ZD ;

Chapman, JM ;

Lehmann, JM ;

Kliewer, SA ;

Willson, TM .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (19) :3785-3788

[2] Structure of the PPARα and -γ ligand binding domain in complex with AZ 242;: Ligand selectivity and agonist activation in the PPAR family [J].

Cronet, P ;

Petersen, JFW ;

Folmer, R ;

Blomberg, N ;

Sjöblom, K ;

Karlsson, U ;

Lindstedt, EL ;

Bamberg, K .

STRUCTURE, 2001, 9 (08) :699-706

[3] Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta [J].

Forman, BM ;

Chen, J ;

Evans, RM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (09) :4312-4317

[4] Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis [J].

Fruchart, JC ;

Duriez, P ;

Staels, B .

CURRENT OPINION IN LIPIDOLOGY, 1999, 10 (03) :245-257

[5] A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression [J].

Heinzel, T ;

Lavinsky, RM ;

Mullen, TM ;

Soderstrom, M ;

Laherty, CD ;

Torchia, J ;

Yang, WM ;

Brard, G ;

Ngo, SD ;

Davie, JR ;

Seto, E ;

Eisenman, RN ;

Rose, DW ;

Glass, CK ;

Rosenfeld, MG .

NATURE, 1997, 387 (6628) :43-48

[6]

ISSEMAN I, 1990, NATURE, V347, P771

[7] PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents [J].

Keller, H ;

Devchand, PR ;

Perroud, M ;

Wahli, W .

BIOLOGICAL CHEMISTRY, 1997, 378 (07) :651-655

[8] Enantio-dependent binding and transactivation of optically active phenylpropanoic acid derivatives at human peroxisome proliferator-activated receptor alpha [J].

Miyachi, H ;

Nomura, M ;

Tanase, T ;

Suzuki, M ;

Murakami, K ;

Awano, K .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (03) :333-335

[9] Design, synthesis and evaluation of substituted phenylpropanoic acid derivatives as peroxisome proliferator-activated receptor (PPAR) activators:: Novel human PPARα-selective activators [J].

Miyachi, H ;

Nomura, M ;

Tanase, T ;

Takahashi, Y ;

Ide, T ;

Tsunoda, M ;

Murakami, K ;

Awano, K .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (01) :77-80

[10]

MURAKAMI K, 2001, 1 INT S PPARS BAS SC

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