Back to Search
Start Over
Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2
- Source :
- ACS Med Chem Lett
- Publication Year :
- 2019
-
Abstract
- [Image: see text] The further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound 1, guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound 28, which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement in vivo was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing.
- Subjects :
- Organic Chemistry
Drug Discovery
Biochemistry
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 10
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- ACS medicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....35560c4673291dc0889ef72ba74bdb91