FXR agonist activity of conformationally constrained analogs of GW 4064

被引：56

作者：

Akwabi-Ameyaw, Adwoa ^{[1
]}

Bass, Jonathan Y. ^{[1
]}

Caldwell, Richard D. ^{[1
]}

Caravella, Justin A. ^{[2
]}

Chen, Lihong ^{[3
]}

Creech, Katrina L. ^{[4
]}

Deaton, David N. ^{[1
]}

Madauss, Kevin P. ^{[2
]}

Marr, Harry B. ^{[5
]}

McFadyen, Robert B. ^{[1
]}

Miller, Aaron B. ^{[2
]}

Navas, Frank, III ^{[1
]}

Parks, Derek J. ^{[6
]}

Spearing, Paul K. ^{[1
]}

Todd, Dan ^{[7
]}

Williams, Shawn P. ^{[2
]}

Wisely, G. Bruce ^{[6
]}

机构：

[1] GlaxoSmithKline Inc, Dept Med Chem, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline Inc, Mol Discovery Res Computat & Struct Chem Res, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline Inc, Dept Metab Dis, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline Inc, Mol Discovery Res Screening & Compound Profiling, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline Inc, Dept Drug Metab & Pharmacokinet, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline Inc, Mol Discovery Res Biol Reagents & Assay Dev, Res Triangle Pk, NC 27709 USA

[7] GlaxoSmithKline Inc, Dept Pharmaceut Dev Phys Properties & Developabil, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 16期

关键词：

Farnesoid X receptor; FXR; Nuclear receptor; FARNESOID-X-RECEPTOR; HEPATIC STELLATE CELLS; TRANS-STILBENE OXIDE; NUCLEAR RECEPTOR; BILE-ACID; LIVER FIBROSIS; DEFICIENT MICE; RAT-LIVER; HOMEOSTASIS; CHOLESTASIS;

D O I：

10.1016/j.bmcl.2009.06.062

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：4733 / 4739

页数：7

共 26 条

[1] Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064 [J].

Akwabi-Ameyaw, Adwoa ;

Bass, Jonathan Y. ;

Caldwell, Richard D. ;

Caravella, Justin A. ;

Chen, Lihong ;

Creech, Katrina L. ;

Deaton, David N. ;

Jones, Stacey A. ;

Kaldor, Istvan ;

Liu, Yaping ;

Madauss, Kevin P. ;

Marr, Harry B. ;

McFadyen, Robert B. ;

Miller, Aaron B. ;

Navas, Frank, III ;

Parks, Derek J. ;

Spearing, Paul K. ;

Todd, Dan ;

Williams, Shawn P. ;

Wisely, G. Bruce .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4339-4343

[2]

AKWABIAMEYAW AA, 2009, Patent No. 005998

[3] Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064 [J].

Bass, Jonathan Y. ;

Caldwell, Richard D. ;

Caravella, Justin A. ;

Chen, Lihong ;

Creech, Katrina L. ;

Deaton, David N. ;

Madauss, Kevin P. ;

Marr, Harry B. ;

McFadyen, Robert B. ;

Miller, Aaron B. ;

Parks, Derek J. ;

Todd, Dan ;

Williams, Shawn P. ;

Wisely, G. Bruce .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (11) :2969-2973

[4] Transient impairment of the adaptive response to fasting in FXR-deficient mice [J].

Cariou, B ;

van Harmelen, K ;

Duran-Sandoval, D ;

van Dijk, T ;

Grefhorst, A ;

Bouchaert, E ;

Fruchart, JC ;

Gonzalez, FJ ;

Kuipers, F ;

Staels, B .

FEBS LETTERS, 2005, 579 (19) :4076-4080

[5] Cross-talk between farnesoid-X-receptor (FXR)and peroxisome proliferator-activated receptor γ contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis [J].

Fiorucci, S ;

Rizzo, G ;

Antonelli, E ;

Renga, B ;

Mencarelli, A ;

Riccardi, L ;

Morelli, A ;

Pruzanski, M ;

Pellicciari, R .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 315 (01) :58-68

[6] Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis [J].

Fiorucci, S ;

Clerici, C ;

Antonelli, E ;

Orlandi, S ;

Goodwin, B ;

Sadeghpour, BM ;

Sabatino, G ;

Russo, G ;

Castellani, D ;

Willson, TM ;

Pruzanski, M ;

Pellicciari, R ;

Morelli, A .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 313 (02) :604-612

[7] A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis [J].

Fiorucci, S ;

Rizzo, G ;

Antonelli, E ;

Renga, B ;

Mencarelli, A ;

Riccardi, L ;

Orlandi, S ;

Pruzanski, M ;

Morelli, A ;

Pellicciari, R .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 314 (02) :584-595

[8] The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis [J].

Fiorucci, S ;

Antonelli, E ;

Rizzo, G ;

Renga, B ;

Mencarelli, A ;

Riccardi, L ;

Orlandi, S ;

Pellicciari, R ;

Morelli, A .

GASTROENTEROLOGY, 2004, 127 (05) :1497-1512

[9] IDENTIFICATION OF A NUCLEAR RECEPTOR THAT IS ACTIVATED BY FARNESOL METABOLITES [J].

FORMAN, BM ;

GOODE, E ;

CHEN, J ;

ORO, AE ;

BRADLEY, DJ ;

PERLMANN, T ;

NOONAN, DJ ;

BURKA, LT ;

MCMORRIS, T ;

LAMPH, WW ;

EVANS, RM ;

WEINBERGER, C .

CELL, 1995, 81 (05) :687-693

[10] Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice [J].

Hanniman, EA ;

Lambert, G ;

McCarthy, TC ;

Sinal, CJ .

JOURNAL OF LIPID RESEARCH, 2005, 46 (12) :2595-2604

← 1 2 3 →