Literature DB >> 26819660

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

Kazuyuki Hirata1, Masayuki Kotoku1, Noriyoshi Seki1, Takaki Maeba1, Katsuya Maeda1, Shintaro Hirashima1, Takayuki Sakai1, Shingo Obika1, Akimi Hori1, Yasunori Hase1, Takayuki Yamaguchi1, Yoshiaki Katsuda1, Takahiro Hata1, Naoki Miyagawa1, Kojo Arita1, Yukihiro Nomura1, Kota Asahina1, Yusuke Aratsu1, Masafumi Kamada2, Tsuyoshi Adachi2, Masato Noguchi2, Satoki Doi2, Paul Crowe3, Erin Bradley3, Ruo Steensma3, Haiyan Tao3, Morgan Fenn3, Robert Babine3, Xiaolin Li3, Scott Thacher3, Hiromasa Hashimoto1, Makoto Shiozaki1.   

Abstract

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.

Entities:  

Keywords:  RORγ; Th17; fraction of sp3 carbon atoms (Fsp3); immunological diseases; ligand efficiency (LE); nuclear receptor

Year:  2015        PMID： 26819660      PMCID： PMC4716592          DOI： 10.1021/acsmedchemlett.5b00253

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


  23 in total

1.  Ligand efficiency: a useful metric for lead selection.

Authors:  Andrew L Hopkins; Colin R Groom; Alexander Alex
Journal:  Drug Discov Today       Date:  2004-05-15       Impact factor: 7.851

2.  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

3.  Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

Authors:  Olivier René; Benjamin P Fauber; Gladys de Leon Boenig; Brenda Burton; Céline Eidenschenk; Christine Everett; Alberto Gobbi; Sarah G Hymowitz; Adam R Johnson; James R Kiefer; Marya Liimatta; Peter Lockey; Maxine Norman; Wenjun Ouyang; Heidi A Wallweber; Harvey Wong
Journal:  ACS Med Chem Lett       Date:  2014-12-04       Impact factor: 4.345

4.  Small molecule amides as potent ROR-γ selective modulators.

Authors:  Pasha M Khan; Bahaa El-Dien M El-Gendy; Naresh Kumar; Ruben Garcia-Ordonez; Li Lin; Claudia H Ruiz; Michael D Cameron; Patrick R Griffin; Theodore M Kamenecka
Journal:  Bioorg Med Chem Lett       Date:  2012-11-22       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.  Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors.

Authors:  Yonghui Wang; Wei Cai; Guifeng Zhang; Ting Yang; Qian Liu; Yaobang Cheng; Ling Zhou; Yingli Ma; Ziqiang Cheng; Sijie Lu; Yong-Gang Zhao; Wei Zhang; Zhijun Xiang; Shuai Wang; Liuqing Yang; Qianqian Wu; Lisa A Orband-Miller; Yan Xu; Jing Zhang; Ruina Gao; Melanie Huxdorf; Jia-Ning Xiang; Zhong Zhong; John D Elliott; Stewart Leung; Xichen Lin
Journal:  Bioorg Med Chem       Date:  2013-12-21       Impact factor: 3.641

7.  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

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.  Escape from flatland: increasing saturation as an approach to improving clinical success.

Authors:  Frank Lovering; Jack Bikker; Christine Humblet
Journal:  J Med Chem       Date:  2009-11-12       Impact factor: 7.446

10.  Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.

Authors:  Christian Gege; Thomas Schlüter; Thomas Hoffmann
Journal:  Bioorg Med Chem Lett       Date:  2014-09-28       Impact factor: 2.823
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  7 in total

1.  N-Arylsulfonyl Indolines as Retinoic Acid Receptor-Related Orphan Receptor γ (RORγ) Agonists.

Authors:  Christelle Doebelin; Rémi Patouret; Ruben D Garcia-Ordonez; Mi Ra Chang; Venkatasubramanian Dharmarajan; Dana S Kuruvilla; Scott J Novick; Li Lin; Michael D Cameron; Patrick R Griffin; Theodore M Kamenecka
Journal:  ChemMedChem       Date:  2016-11-23       Impact factor: 3.466

2.  Structural studies unravel the active conformation of apo RORγt nuclear receptor and a common inverse agonism of two diverse classes of RORγt inhibitors.

Authors:  Xiang Li; Marie Anderson; Delphine Collin; Ingo Muegge; John Wan; Debra Brennan; Stanley Kugler; Donna Terenzio; Charles Kennedy; Siqi Lin; Mark E Labadia; Brian Cook; Robert Hughes; Neil A Farrow
Journal:  J Biol Chem       Date:  2017-05-25       Impact factor: 5.157

3.  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

4.  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

5.  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

Review 6.  Cyclobutanes in Small-Molecule Drug Candidates.

Authors:  Marnix R van der Kolk; Mathilde A C H Janssen; Floris P J T Rutjes; Daniel Blanco-Ania
Journal:  ChemMedChem       Date:  2022-03-29       Impact factor: 3.540

7.  Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C-H activation and C-C bond formation.

Authors:  Nehaal Ahmed; Richard J Spears; Tom D Sheppard; Vijay Chudasama
Journal:  Chem Sci       Date:  2022-06-27       Impact factor: 9.969
  7 in total

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