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1.
J Med Chem ; 67(2): 952-970, 2024 01 25.
Article in English | MEDLINE | ID: mdl-38170624

ABSTRACT

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

2.
Genes Cells ; 22(6): 535-551, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28493531

ABSTRACT

Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.


Subject(s)
Nuclear Receptor Co-Repressor 2/metabolism , Nuclear Receptor Coactivator 1/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Binding Sites , Humans , Hydrogen Bonding , Models, Molecular , Mutation , Nuclear Receptor Co-Repressor 2/agonists , Nuclear Receptor Co-Repressor 2/chemistry , Nuclear Receptor Co-Repressor 2/genetics , Nuclear Receptor Coactivator 1/chemistry , Nuclear Receptor Coactivator 1/genetics , Peptide Fragments , Protein Binding , Protein Conformation , Triterpenes/pharmacology , Ursolic Acid
3.
ACS Med Chem Lett ; 7(1): 23-7, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26819660

ABSTRACT

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.

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