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
- Deposit:2020-06-18
- Modify:2022-08-30
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.
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
- PubChem
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