Literature DB >> 30776227

Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold.

Masayuki Kotoku1, Takaki Maeba, Shingo Fujioka, Masahiro Yokota, Noriyoshi Seki, Keisuke Ito, Yoshihiro Suwa, Taku Ikenogami, Kazuyuki Hirata, Yasunori Hase, Yoshiaki Katsuda, Naoki Miyagawa, Kojo Arita, Kota Asahina, Masato Noguchi, Akihiro Nomura, Satoki Doi, Tsuyoshi Adachi, Paul Crowe2, Haiyan Tao2, Scott Thacher2, Hiromasa Hashimoto, Takayoshi Suzuki1, Makoto Shiozaki.   

Abstract

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

Entities:  

Year:  2019        PMID： 30776227     DOI： 10.1021/acs.jmedchem.8b01567

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  8 in total

1.  Synthesis of α-substituted 2-(1H-1,2,4-triazol-3-yl)acetates and 5-amino-2,4-dihydro-3H-pyrazol-3-ones via the Pinner strategy.

Authors:  Dmytro M Khomenko; Roman O Doroshchuk; Hanna V Ivanova; Borys V Zakharchenko; Ilona V Raspertova; Oleksandr V Vaschenko; Sergiu Shova; Alexey V Dobrydnev; Yurii S Moroz; Oleksandr O Grygorenko; Rostyslav D Lampeka
Journal:  Tetrahedron Lett       Date:  2021-03-02       Impact factor: 2.032

2.  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

3.  Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357.

Authors:  Christian Harcken; Johanna Csengery; Michael Turner; Lifen Wu; Shuang Liang; Robert Sibley; Steven Brunette; Mark Labadia; Kathleen Hoyt; Anita Wayne; Thomas Wieckowski; Gregg Davis; Mark Panzenbeck; Donald Souza; Stanley Kugler; Donna Terenzio; Delphine Collin; Dustin Smith; Ryan M Fryer; Yin-Chao Tseng; Jörg P Hehn; Kim Fletcher; Robert O Hughes
Journal:  ACS Med Chem Lett       Date:  2021-01-05       Impact factor: 4.345

4.  A molecular switch regulating transcriptional repression and activation of PPARγ.

Authors:  Jinsai Shang; Sarah A Mosure; Jie Zheng; Richard Brust; Jared Bass; Ashley Nichols; Laura A Solt; Patrick R Griffin; Douglas J Kojetin
Journal:  Nat Commun       Date:  2020-02-19       Impact factor: 14.919

Review 5.  Recent advances in modulators of circadian rhythms: an update and perspective.

Authors:  Shenzhen Huang; Xinwei Jiao; Dingli Lu; Xiaoting Pei; Di Qi; Zhijie Li
Journal:  J Enzyme Inhib Med Chem       Date:  2020-12       Impact factor: 5.051

6.  Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt.

Authors:  Rens M J M de Vries; Femke A Meijer; Richard G Doveston; Iris A Leijten-van de Gevel; Luc Brunsveld
Journal:  Proc Natl Acad Sci U S A       Date:  2021-02-09       Impact factor: 11.205

7.  Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand.

Authors:  Femke A Meijer; Guido J M Oerlemans; Luc Brunsveld
Journal:  ACS Chem Biol       Date:  2021-02-17       Impact factor: 5.100

8.  Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists.

Authors:  Femke A Meijer; Richard G Doveston; Rens M J M de Vries; Gaël M Vos; Alex A A Vos; Seppe Leysen; Marcel Scheepstra; Christian Ottmann; Lech-Gustav Milroy; Luc Brunsveld
Journal:  J Med Chem       Date:  2019-12-24       Impact factor: 7.446
  8 in total

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