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Inverse agonist activity at His6-tcs-human RORalpha LBD assessed as inhibition of biotinylated PGC1alpha (130 to 154 residues) peptide recruitment incubated for 1 hr by HTRF-FRET assay

PubChem AID
1357030
Primary Citation
Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design [PMID: 30095900]
Source
External ID
BioAssay Type
Confirmatory
Tested Substances
Tested Compounds
Version
Status
Live
Dates
  • Deposit:
    2020-06-18
  • Modify:
    2022-08-30
Description
This bioassay record (AID 1357030) reports results from the above primary citation. Additional data from the same publication are reported in a total of 52 BioAssay records in PubChem.

1 Description

Title: Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.

Abstract: Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-TH17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.

2 Comment

Compounds with activity <= 10uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Journal: J Med Chem

Year: 2018

Volume: 61

Issue: 17

First Page: 7796

Last Page: 7813

DOI: 10.1021/acs.jmedchem.8b00783

Target ChEMBL ID: CHEMBL5868

ChEMBL Target Name: Nuclear receptor ROR-alpha

ChEMBL Target Type: SINGLE PROTEIN - Target is a single protein chain

Relationship Type: D - Direct protein target assigned

Confidence: Direct single protein target assigned

3 Result Definitions

4 Data Table

5 Target

8 Identity

8.1 BioAssay Name

Inverse agonist activity at His6-tcs-human RORalpha LBD assessed as inhibition of biotinylated PGC1alpha (130 to 154 residues) peptide recruitment incubated for 1 hr by HTRF-FRET assay

8.2 Source

8.3 External ID

8.4 Project Category

Literature, Extracted

8.5 BioAssay Type

Confirmatory

8.6 Deposit Date

2020-06-18

8.7 Modify Date

Version 1.1
Version 2.1
2022-08-30 (currently shown)

8.8 Status

Live

9 Same-Publication BioAssays

10 BioAssay Annotations

Assay Type
Binding
Assay Organism

11 Information Sources

  1. PubChem
  2. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
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