Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists

被引：9

作者：

Schmidt, Jurema ^{[1
]}

Schierle, Simone ^{[1
]}

Gellrich, Leonie ^{[1
]}

Kaiser, Astrid ^{[1
]}

Merk, Daniel ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Max von Laue Str 9, D-60438 Frankfurt, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 14期

关键词：

Metabolic syndrome; Non-alcoholic steatohepatitis; Nuclear receptor modulator; Bile acid receptor; ANTHRANILIC ACID-DERIVATIVES; FXR ANTAGONISTS; MEDICINAL CHEMISTRY; NUCLEAR RECEPTOR; BILE-ACIDS; POTENT; MODULATORS; DISCOVERY; LIGANDS; IDENTIFICATION;

D O I：

10.1016/j.bmc.2018.07.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Activation of the nuclear farnesoid X receptor (FXR) which acts as cellular bile acid sensor has been validated as therapeutic strategy to counter liver disorders such as non-alcoholic steatohepatitis by the clinical efficacy of obeticholic acid. FXR antagonism, in contrast, is less well studied and potent small molecule FXR antagonists are rare. Here we report the systematic optimization of a novel class of FXR antagonists towards low nanomolar potency. The most optimized compound antagonizes baseline and agonist induced FXR activity in a full length FXR reporter gene assay and represses intrinsic expression of FXR regulated genes in hepatoma cells. With this activity and a favorable toxicity-, stability- and selectivity-profile it appears suitable to further study FXR antagonism in vitro and in vivo.

引用

页码：4240 / 4253

页数：14

共 34 条

[21]

Merk D, 2012, FUTURE MED CHEM, V4, P1015, DOI [10.4155/FMC.12.47, 10.4155/fmc.12.47]

[22] Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial [J].

Neuschwander-Tetri, Brent A. ;

Loomba, Rohit ;

Sanyal, Arun J. ;

Lavine, Joel E. ;

Van Natta, Mark L. ;

Abdelmalek, Manal F. ;

Chalasani, Naga ;

Dasarathy, Srinivasan ;

Diehl, Anna Mae ;

Hameed, Bilal ;

Kowdley, Kris V. ;

McCullough, Arthur ;

Terrault, Norah ;

Clark, Jeanne M. ;

Tonascia, James ;

Brunt, Elizabeth M. ;

Kleiner, David E. ;

Doo, Edward .

LANCET, 2015, 385 (9972) :956-965

[23] Bile acids: Natural ligands for an orphan nuclear receptor [J].

Parks, DJ ;

Blanchard, SG ;

Bledsoe, RK ;

Chandra, G ;

Consler, TG ;

Kliewer, SA ;

Stimmel, JB ;

Willson, TM ;

Zavacki, AM ;

Moore, DD ;

Lehmann, JM .

SCIENCE, 1999, 284 (5418) :1365-1368

[24] Carnosic acid and carnosol, phenolic diterpene compounds of the labiate herbs rosemary and sage, are activators of the human peroxisome proliferator-activated receptor gamma [J].

Rau, Oliver ;

Wurglics, Mario ;

Paulke, Alexander ;

Zitzkowski, Jessica ;

Meindl, Nadine ;

Bock, Andreas ;

Dingermann, Theodor ;

Abdel-Tawab, Mona ;

Schubert-Zsilavecz, Manfred .

PLANTA MEDICA, 2006, 72 (10) :881-887

[25] ISOLATION OF PROTEINS THAT INTERACT SPECIFICALLY WITH THE RETINOID-X RECEPTOR - 2 NOVEL ORPHAN RECEPTORS [J].

SEOL, WG ;

CHOI, HS ;

MOORE, DD .

MOLECULAR ENDOCRINOLOGY, 1995, 9 (01) :72-85

[26] Functional characterization of vitamin D responding regions in the human 5-Lipoxygenase gene [J].

Seuter, Sabine ;

Vaisanen, Sami ;

Radmark, Olof ;

Carlberg, Carsten ;

Steinhilber, Dieter .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2007, 1771 (07) :864-872

[27] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity [J].

Steri, Ramona ;

Achenbach, Janosch ;

Steinhilber, Dieter ;

Schubert-Zsilavecz, Manfred ;

Proschak, Ewgenij .

BIOCHEMICAL PHARMACOLOGY, 2012, 83 (12) :1674-1681

[28] Nonacidic Chemotype Possessing N-Acylated Piperidine Moiety as Potent Farnesoid X Receptor (FXR) Antagonists [J].

Teno, Naoki ;

Yamashita, Yukiko ;

Ig, Yusuke ;

Fujimori, Ko ;

Une, Mizuho ;

Nishimaki-Mogami, Tomoko ;

Hiramoto, Takie ;

Gohda, Keigo .

ACS MEDICINAL CHEMISTRY LETTERS, 2018, 9 (02) :78-83

[29] Firefly Luciferase in Chemical Biology: A Compendium of Inhibitors, Mechanistic Evaluation of Chemotypes, and Suggested Use As a Reporter [J].

Thorne, Natasha ;

Shen, Min ;

Lea, Wendy A. ;

Simeonov, Anton ;

Lovell, Scott ;

Auld, Douglas S. ;

Inglese, James .

CHEMISTRY & BIOLOGY, 2012, 19 (08) :1060-1072

[30] Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH) [J].

Tully, David C. ;

Rucker, Paul V. ;

Chianelli, Donatella ;

Williams, Jennifer ;

Vidal, Agnes ;

Alper, Phil B. ;

Mutnick, Daniel ;

Bursulaya, Badry ;

Schmeits, James ;

Wu, Xiangdong ;

Bao, Dingjiu ;

Zoll, Jocelyn ;

Kim, Young ;

Groessl, Todd ;

McNamara, Peter ;

Seidel, H. Martin ;

Molteni, Valentina ;

Liu, Bo ;

Phimister, Andrew ;

Joseph, Sean B. ;

Laffitte, Bryan .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (24) :9960-9973

← 1 2 3 4 →