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
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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