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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.
J Med Chem ; 63(13): 7163-7185, 2020 07 09.
Article in English | MEDLINE | ID: mdl-32511913

ABSTRACT

Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and antidermatitis efficacy in the animal models. One of these compounds, JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clinical trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.


Subject(s)
Dermatitis, Atopic/drug therapy , Dermatologic Agents/pharmacology , Drug Design , Janus Kinase Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Pyrroles/pharmacology , Dermatologic Agents/therapeutic use , Humans , Inhibitory Concentration 50 , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/chemistry , Models, Molecular , Protein Conformation , Pyrroles/therapeutic use
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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