Identification of novel quinazolinedione derivatives as RORγt inverse agonist
Autor: | Junya Shirai, Yoshiyuki Fukase, Keiko Koga, Ryoukichi Koyama, Hideyuki Nakagawa, Isaac Hoffman, Bi-Ching Sang, Mitsunori Kono, Toshitake Okui, Satoshi Yamamoto, Yasushi Fujitani, Masaharu Nakayama, Yoshihide Tomata, Robert J. Skene, Kazuko Yonemori, Atsuko Ochida, Masashi Yamasaki, Ayumu Sato |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Encephalomyelitis Autoimmune Experimental Drug Inverse Agonism Clinical Biochemistry Retinoic acid Administration Oral Pharmaceutical Science Pharmacology Biochemistry Inhibitory Concentration 50 Jurkat Cells Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine RAR-related orphan receptor gamma Oral administration Drug Discovery medicine Animals Humans Inverse agonist Moiety Molecular Biology Quinazolinones Binding Sites Chemistry Interleukin-17 Organic Chemistry Experimental autoimmune encephalomyelitis Nuclear Receptor Subfamily 1 Group F Member 3 medicine.disease Small molecule Protein Structure Tertiary Rats Molecular Docking Simulation 030104 developmental biology Solubility Rats Inbred Lew 030220 oncology & carcinogenesis Th17 Cells Molecular Medicine Female Interleukin 17 Protein Binding |
Zdroj: | Bioorganic & Medicinal Chemistry. 26:721-736 |
ISSN: | 0968-0896 |
Popis: | Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed. |
Databáze: | OpenAIRE |
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