Literature DB >> 26191367

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

Yonghui Wang1, Wei Cai2, Yaobang Cheng2, Ting Yang2, Qian Liu2, Guifeng Zhang2, Qinghua Meng2, Fangbin Han2, Yafei Huang1, Ling Zhou2, Zhijun Xiang2, Yong-Gang Zhao2, Yan Xu2, Ziqiang Cheng2, Sijie Lu2, Qianqian Wu2, Jia-Ning Xiang2, John D Elliott2, Stewart Leung2, Feng Ren2, Xichen Lin2.   

Abstract

A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure-activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.

Entities:  

Keywords:  EAE; RORγt inhibitor; Th17 cell differentiation; biaryl amides; multiple sclerosis

Year:  2015        PMID： 26191367      PMCID： PMC4499822          DOI： 10.1021/acsmedchemlett.5b00122

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


  35 in total

1.  Identification of tertiary sulfonamides as RORc inverse agonists.

Authors:  Benjamin P Fauber; Olivier René; Brenda Burton; Christine Everett; Alberto Gobbi; Julie Hawkins; Adam R Johnson; Marya Liimatta; Peter Lockey; Maxine Norman; Harvey Wong
Journal:  Bioorg Med Chem Lett       Date:  2014-03-21       Impact factor: 2.823

2.  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

3.  Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2.

Authors:  Xiaohu Wang; Yibing Zhang; Xuexian O Yang; Roza I Nurieva; Seon Hee Chang; Sandra S Ojeda; Hong S Kang; Kimberly S Schluns; Jianfang Gui; Anton M Jetten; Chen Dong
Journal:  Immunity       Date:  2012-01-12       Impact factor: 31.745

4.  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

5.  IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.

Authors:  Yutaka Komiyama; Susumu Nakae; Taizo Matsuki; Aya Nambu; Harumichi Ishigame; Shigeru Kakuta; Katsuko Sudo; Yoichiro Iwakura
Journal:  J Immunol       Date:  2006-07-01       Impact factor: 5.422

6.  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 7.  Targeting Th17 cells in autoimmune diseases.

Authors:  Jianfei Yang; Mark S Sundrud; Jill Skepner; Tetsuya Yamagata
Journal:  Trends Pharmacol Sci       Date:  2014-08-14       Impact factor: 14.819

8.  Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors.

Authors:  Jun R Huh; Erika E Englund; Hang Wang; Ruili Huang; Pengxiang Huang; Fraydoon Rastinejad; James Inglese; Christopher P Austin; Ronald L Johnson; Wenwei Huang; Dan R Littman
Journal:  ACS Med Chem Lett       Date:  2013-01-10       Impact factor: 4.345

9.  Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.

Authors:  Laura A Solt; Naresh Kumar; Philippe Nuhant; Yongjun Wang; Janelle L Lauer; Jin Liu; Monica A Istrate; Theodore M Kamenecka; William R Roush; Dušica Vidović; Stephan C Schürer; Jihong Xu; Gail Wagoner; Paul D Drew; Patrick R Griffin; Thomas P Burris
Journal:  Nature       Date:  2011-04-17       Impact factor: 49.962

10.  The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.

Authors:  Nicolas Manel; Derya Unutmaz; Dan R Littman
Journal:  Nat Immunol       Date:  2008-05-04       Impact factor: 25.606
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  13 in total

1.  Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2.

Authors:  Stefan von Berg; Yafeng Xue; Mia Collins; Antonio Llinas; Roine I Olsson; Torbjörn Halvarsson; Maria Lindskog; Jesper Malmberg; Johan Jirholt; Nina Krutrök; Marie Ramnegård; Marie Brännström; Anders Lundqvist; Matti Lepistö; Anna Aagaard; Jane McPheat; Eva L Hansson; Rongfeng Chen; Yao Xiong; Thomas G Hansson; Frank Narjes
Journal:  ACS Med Chem Lett       Date:  2019-05-29       Impact factor: 4.345

2.  ILC3-derived OX40L is essential for homeostasis of intestinal Tregs in immunodeficient mice.

Authors:  Tian Deng; Caixia Suo; Jiali Chang; Rui Yang; Jingyu Li; Ting Cai; Ju Qiu
Journal:  Cell Mol Immunol       Date:  2019-02-13       Impact factor: 11.530

3.  Analysis of the Transcriptional Activity of Retinoic Acid-Related Orphan Receptors (RORs) and Inhibition by Inverse Agonists.

Authors:  Yukimasa Takeda; Hong Soon Kang; Anton M Jetten
Journal:  Methods Mol Biol       Date:  2019

4.  Molecular dynamics simulations on RORγt: insights into its functional agonism and inverse agonism.

Authors:  Cong-Min Yuan; Hai-Hong Chen; Nan-Nan Sun; Xiao-Jun Ma; Jun Xu; Wei Fu
Journal:  Acta Pharmacol Sin       Date:  2019-07-17       Impact factor: 6.150

5.  Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ.

Authors:  Bill Pham; Ziju Cheng; Daniel Lopez; Richard J Lindsay; David Foutch; Rily T Majors; Tongye Shen
Journal:  Front Mol Biosci       Date:  2022-06-15

6.  Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists.

Authors:  Ryota Nakajima; Hiroyuki Oono; Sakae Sugiyama; Yohei Matsueda; Tomohide Ida; Shinji Kakuda; Jun Hirata; Atsushi Baba; Akito Makino; Ryo Matsuyama; Ryan D White; Ryan Ρ Wurz; Youngsook Shin; Xiaoshan Min; Angel Guzman-Perez; Zhulun Wang; Antony Symons; Sanjay K Singh; Srinivasa Reddy Mothe; Sergei Belyakov; Anjan Chakrabarti; Satoshi Shuto
Journal:  ACS Med Chem Lett       Date:  2020-02-27       Impact factor: 4.345

7.  From RORγt Agonist to Two Types of RORγt Inverse Agonists.

Authors:  Yonghui Wang; Wei Cai; Ting Tang; Qian Liu; Ting Yang; Liuqing Yang; Yingli Ma; Guifeng Zhang; Yafei Huang; Xiaoxia Song; Lisa A Orband-Miller; Qianqian Wu; Ling Zhou; Zhijun Xiang; Jia-Ning Xiang; Stewart Leung; Liming Shao; Xichen Lin; Mercedes Lobera; Feng Ren
Journal:  ACS Med Chem Lett       Date:  2018-01-22       Impact factor: 4.345

8.  Retinoic acid-related Orphan Receptor γ (RORγ): connecting sterol metabolism to regulation of the immune system and autoimmune disease.

Authors:  Anton M Jetten; Yukimasa Takeda; Andrzej Slominski; Hong Soon Kang
Journal:  Curr Opin Toxicol       Date:  2018-02-01

9.  Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand.

Authors:  Douglas J Marcotte; YuTing Liu; Kevin Little; John H Jones; Noel A Powell; Craig P Wildes; Laura F Silvian; Jayanth V Chodaparambil
Journal:  BMC Struct Biol       Date:  2016-06-01

10.  Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction.

Authors:  Masato Noguchi; Akihiro Nomura; Satoki Doi; Keishi Yamaguchi; Kazuyuki Hirata; Makoto Shiozaki; Katsuya Maeda; Shintaro Hirashima; Masayuki Kotoku; Takayuki Yamaguchi; Yoshiaki Katsuda; Paul Crowe; Haiyan Tao; Scott Thacher; Tsuyoshi Adachi
Journal:  Sci Rep       Date:  2018-11-26       Impact factor: 4.379
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