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Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design
- Source :
- Journal of Medicinal Chemistry. 61:7796-7813
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
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 favorab...
- Subjects :
- Models, Molecular
0301 basic medicine
Drug Inverse Agonism
Protein Conformation
Stereochemistry
Administration, Oral
Biological Availability
Rodentia
Crystallography, X-Ray
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Amide
Acetamides
Drug Discovery
Animals
Humans
Inverse agonist
Structure–activity relationship
Tissue Distribution
Binding site
Cells, Cultured
Orphan receptor
Binding Sites
Molecular Structure
Interleukin-17
Nuclear Receptor Subfamily 1, Group F, Member 3
Retinoic acid receptor
030104 developmental biology
chemistry
Drug Design
Th17 Cells
Molecular Medicine
Acetamide
Protein Binding
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....42539d4567cc086bb6e06886316ba550