Literature DB >> 24040486

Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors.

Jun R Huh1, Erika E Englund, Hang Wang, Ruili Huang, Pengxiang Huang, Fraydoon Rastinejad, James Inglese, Christopher P Austin, Ronald L Johnson, Wenwei Huang, Dan R Littman.   

Abstract

Retinoic acid-related orphan receptor RORγt plays a pivotal role in the differentiation of TH17 cells. Antagonizing RORγt transcriptional activity is a potential means to treat TH17-related autoimmune diseases. Herein, we describe the identification of a series of diphenylpropanamides as novel and selective RORγ antagonists. Diphenylpropanamide 4n inhibited transcriptional activity of RORγt, but not RORα, in cells. In addition, it suppressed human TH17 cell differentiation at sub-micromolar concentrations.

Entities:  

Keywords:  RORγ antagonist; Retinoic acid-related orphan receptor; TH17-related autoimmune diseases; diphenylpropanamide

Year:  2013        PMID： 24040486      PMCID： PMC3770298          DOI： 10.1021/ml300286h

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  22 in total

Review 1.  Development in motion: helper T cells at work.

Authors:  Steven L Reiner
Journal:  Cell       Date:  2007-04-06       Impact factor: 41.582

2.  Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma.

Authors:  Lihua Jin; Dariusz Martynowski; Songyang Zheng; Taira Wada; Wen Xie; Yong Li
Journal:  Mol Endocrinol       Date:  2010-03-04

3.  Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein.

Authors:  Tao Xu; Xiaohu Wang; Bo Zhong; Roza I Nurieva; Sheng Ding; Chen Dong
Journal:  J Biol Chem       Date:  2011-05-12       Impact factor: 5.157

4.  Facile synthesis and biological evaluation of 3,3-diphenylpropanoyl piperazines as T-type calcium channel blockers.

Authors:  Yeon-hee Choi; Du Jong Baek; Seon Hee Seo; Jae Kyun Lee; Ae Nim Pae; Yong Seo Cho; Sun-Joon Min
Journal:  Bioorg Med Chem Lett       Date:  2010-11-12       Impact factor: 2.823

5.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

Authors:  Ivaylo I Ivanov; Brent S McKenzie; Liang Zhou; Carlos E Tadokoro; Alice Lepelley; Juan J Lafaille; Daniel J Cua; Dan R Littman
Journal:  Cell       Date:  2006-09-22       Impact factor: 41.582

6.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.

Authors:  David Yen; Jeanne Cheung; Heleen Scheerens; Frédérique Poulet; Terrill McClanahan; Brent McKenzie; Melanie A Kleinschek; Alex Owyang; Jeanine Mattson; Wendy Blumenschein; Erin Murphy; Manjiri Sathe; Daniel J Cua; Robert A Kastelein; Donna Rennick
Journal:  J Clin Invest       Date:  2006-05       Impact factor: 14.808

7.  Pd(II)-bipyridine catalyzed conjugate addition of arylboronic acid to alpha,beta-unsaturated carbonyl compounds.

Authors:  Xiyan Lu; Shaohui Lin
Journal:  J Org Chem       Date:  2005-11-11       Impact factor: 4.354

8.  Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands.

Authors:  Yongjun Wang; Naresh Kumar; Laura A Solt; Timothy I Richardson; Leah M Helvering; Christine Crumbley; Ruben D Garcia-Ordonez; Keith R Stayrook; Xi Zhang; Scott Novick; Michael J Chalmers; Patrick R Griffin; Thomas P Burris
Journal:  J Biol Chem       Date:  2009-12-04       Impact factor: 5.157

9.  Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity.

Authors:  Jun R Huh; Monica W L Leung; Pengxiang Huang; Daniel A Ryan; Michael R Krout; Raghu R V Malapaka; Jonathan Chow; Nicolas Manel; Maria Ciofani; Sangwon V Kim; Adolfo Cuesta; Fabio R Santori; Juan J Lafaille; H Eric Xu; David Y Gin; Fraydoon Rastinejad; Dan R Littman
Journal:  Nature       Date:  2011-03-27       Impact factor: 49.962

Review 10.  Small molecule inhibitors of RORγt: targeting Th17 cells and other applications.

Authors:  Jun R Huh; Dan R Littman
Journal:  Eur J Immunol       Date:  2012-09       Impact factor: 5.532
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  18 in total

1.  SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor.

Authors:  Kazuyuki Hirata; Masayuki Kotoku; Noriyoshi Seki; Takaki Maeba; Katsuya Maeda; Shintaro Hirashima; Takayuki Sakai; Shingo Obika; Akimi Hori; Yasunori Hase; Takayuki Yamaguchi; Yoshiaki Katsuda; Takahiro Hata; Naoki Miyagawa; Kojo Arita; Yukihiro Nomura; Kota Asahina; Yusuke Aratsu; Masafumi Kamada; Tsuyoshi Adachi; Masato Noguchi; Satoki Doi; Paul Crowe; Erin Bradley; Ruo Steensma; Haiyan Tao; Morgan Fenn; Robert Babine; Xiaolin Li; Scott Thacher; Hiromasa Hashimoto; Makoto Shiozaki
Journal:  ACS Med Chem Lett       Date:  2015-11-04       Impact factor: 4.345

2.  Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.

Authors:  Yoon Seok Choi; Min Kyung Jung; Jeewon Lee; Seong Jin Choi; Sung Hoon Choi; Hyun Woong Lee; Jong-Joo Lee; Hyung Joon Kim; Sang Hoon Ahn; Dong Hyeon Lee; Won Kim; Su-Hyung Park; Jun R Huh; Hyoung-Pyo Kim; Jun Yong Park; Eui-Cheol Shin
Journal:  Gastroenterology       Date:  2017-12-09       Impact factor: 22.682

3.  RORγt expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses.

Authors:  M A Kluger; A Nosko; T Ramcke; B Goerke; M C Meyer; C Wegscheid; M Luig; G Tiegs; R A K Stahl; O M Steinmetz
Journal:  Clin Exp Immunol       Date:  2017-01-05       Impact factor: 4.330

4.  Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists.

Authors:  Ting Yang; Qian Liu; Yaobang Cheng; Wei Cai; Yingli Ma; Liuqing Yang; Qianqian Wu; Lisa A Orband-Miller; Ling Zhou; Zhijun Xiang; Melanie Huxdorf; Wei Zhang; Jing Zhang; Jia-Ning Xiang; Stewart Leung; Yang Qiu; Zhong Zhong; John D Elliott; Xichen Lin; Yonghui Wang
Journal:  ACS Med Chem Lett       Date:  2013-11-22       Impact factor: 4.345

Review 5.  Regulation of RORγt in Inflammatory Lymphoid Cell Differentiation.

Authors:  Wendy Huang; Dan R Littman
Journal:  Cold Spring Harb Symp Quant Biol       Date:  2016-03-11

Review 6.  ROR nuclear receptors: structures, related diseases, and drug discovery.

Authors:  Yan Zhang; Xiao-yu Luo; Dong-hai Wu; Yong Xu
Journal:  Acta Pharmacol Sin       Date:  2014-12-15       Impact factor: 6.150

7.  Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors.

Authors:  Yonghui Wang; Wei Cai; Yaobang Cheng; Ting Yang; Qian Liu; Guifeng Zhang; Qinghua Meng; Fangbin Han; Yafei Huang; Ling Zhou; Zhijun Xiang; Yong-Gang Zhao; Yan Xu; Ziqiang Cheng; Sijie Lu; Qianqian Wu; Jia-Ning Xiang; John D Elliott; Stewart Leung; Feng Ren; Xichen Lin
Journal:  ACS Med Chem Lett       Date:  2015-05-26       Impact factor: 4.345

8.  RORγt(+)Foxp3(+) Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN.

Authors:  Malte A Kluger; Matthias C Meyer; Anna Nosko; Boeren Goerke; Michael Luig; Claudia Wegscheid; Gisa Tiegs; Rolf A K Stahl; Ulf Panzer; Oliver M Steinmetz
Journal:  J Am Soc Nephrol       Date:  2015-06-08       Impact factor: 10.121

Review 9.  Therapeutic Potential of IL-17-Mediated Signaling Pathway in Autoimmune Liver Diseases.

Authors:  Haiyan Zhang; Francesca Bernuzzi; Ana Lleo; Xiong Ma; Pietro Invernizzi
Journal:  Mediators Inflamm       Date:  2015-06-04       Impact factor: 4.711

Review 10.  Targeting Th17 Cells with Small Molecules and Small Interference RNA.

Authors:  Hui Lin; Pingfang Song; Yi Zhao; Li-Jia Xue; Yi Liu; Cong-Qiu Chu
Journal:  Mediators Inflamm       Date:  2015-12-17       Impact factor: 4.711
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