Literature DB >> 26048793

Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists.

Benjamin P Fauber1, Alberto Gobbi2, Kirk Robarge2, Aihe Zhou2, Adrian Barnard3, Jianhua Cao4, Yuzhong Deng2, Céline Eidenschenk2, Christine Everett2, Arunima Ganguli3, Julie Hawkins3, Adam R Johnson2, Hank La2, Maxine Norman3, Gary Salmon3, Susan Summerhill3, Wenjun Ouyang2, Wei Tang4, Harvey Wong2.   

Abstract

The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  GNE-0946; GNE-6468; IL-17; PPARγ; RORc; RORγ

Mesh：

Substances：

Year:  2015        PMID： 26048793     DOI： 10.1016/j.bmcl.2015.05.055

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  10 in total

1.  Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases.

Authors:  Hongjun Zhang; Blair T Lapointe; Neville Anthony; Rita Azevedo; Jos Cals; Craig C Correll; Matthew Daniels; Sujal Deshmukh; Hans van Eenenaam; Heidi Ferguson; Laxminarayan G Hegde; Willem Jan Karstens; John Maclean; J Richard Miller; Lily Y Moy; Vladimir Simov; Sunil Nagpal; Arthur Oubrie; Rachel L Palte; Gopal Parthasarathy; Nunzio Sciammetta; Mario van der Stelt; Janice D Woodhouse; B Wesley Trotter; Kenneth Barr
Journal:  ACS Med Chem Lett       Date:  2020-01-09       Impact factor: 4.345

2.  Delineation of the molecular determinants of the unique allosteric binding site of the orphan nuclear receptor RORγt.

Authors:  Iris A Leijten-van de Gevel; Luc Brunsveld
Journal:  J Biol Chem       Date:  2020-05-20       Impact factor: 5.157

3.  Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt.

Authors:  Femke A Meijer; Annet O W M Saris; Richard G Doveston; Guido J M Oerlemans; Rens M J M de Vries; Bente A Somsen; Anke Unger; Bert Klebl; Christian Ottmann; Peter J Cossar; Luc Brunsveld
Journal:  J Med Chem       Date:  2021-05-19       Impact factor: 7.446

4.  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

5.  Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site.

Authors:  Femke A Meijer; Maxime C M van den Oetelaar; Richard G Doveston; Ella N R Sampers; Luc Brunsveld
Journal:  ACS Med Chem Lett       Date:  2021-03-08       Impact factor: 4.345

6.  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

7.  Electrochemical [4 + 1] Tandem sp3(C-H) Double Amination for the Direct Synthesis of 3-Acyl-Functionalized Imidazo[1,5-a]pyridines.

Authors:  Qiang Wang; Xia Yao; Xian-Jing Xu; Shuai Zhang; Lei Ren
Journal:  ACS Omega       Date:  2022-01-27

8.  Anomeric Stereoauxiliary Cleavage of the C-N Bond of d-Glucosamine for the Preparation of Imidazo[1,5-a]pyridines.

Authors:  Kui Zeng; Jin Ye; Xintong Meng; Sebastian Dechert; Martin Simon; Shuaiyu Gong; Ricardo A Mata; Kai Zhang
Journal:  Chemistry       Date:  2022-04-08       Impact factor: 5.020

9.  Regulation of Circadian Genes Nr1d1 and Nr1d2 in Sex-Different Manners during Liver Aging.

Authors:  Sang Gyun Noh; Hee Jin Jung; Seungwoo Kim; Radha Arulkumar; Dae Hyun Kim; Daeui Park; Hae Young Chung
Journal:  Int J Mol Sci       Date:  2022-09-02       Impact factor: 6.208

10.  Identification of an allosteric binding site for RORγt inhibition.

Authors:  Marcel Scheepstra; Seppe Leysen; Geert C van Almen; J Richard Miller; Jennifer Piesvaux; Victoria Kutilek; Hans van Eenennaam; Hongjun Zhang; Kenneth Barr; Sunil Nagpal; Stephen M Soisson; Maria Kornienko; Kristen Wiley; Nathaniel Elsen; Sujata Sharma; Craig C Correll; B Wesley Trotter; Mario van der Stelt; Arthur Oubrie; Christian Ottmann; Gopal Parthasarathy; Luc Brunsveld
Journal:  Nat Commun       Date:  2015-12-07       Impact factor: 14.919
  10 in total

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