Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitor, S18-000003
| Autor: | Masahide Odan, Shiho Yamamoto, Takayo Haruna, Shiro Kida, Yoshikazu Sasaki, Ayahisa Watanabe, Masaya Shimizu, Takayuki Okuno, Azumi Ueyama |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Drug Evaluation Preclinical Retinoic acid Administration Oral Pharmaceutical Science Molecular Dynamics Simulation Pharmacology Crystallography X-Ray Binding Competitive Interleukin-23 Biochemistry Autoimmune Diseases Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Oral administration RAR-related orphan receptor gamma Drug Discovery medicine Animals Humans Molecular Biology Transcription factor Skin Autoimmune disease Orphan receptor Binding Sites Interleukin-17 Organic Chemistry Nuclear Receptor Subfamily 1 Group F Member 3 medicine.disease Amides Rats Retinoic acid receptor 030104 developmental biology chemistry Th17 Cells Molecular Medicine Interleukin 17 Half-Life Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:3549-3553 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2018.09.032 |
| Popis: | The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect