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Your search keyword '"Atsuko Ochida"' showing total 2 results
Start Over Author "Atsuko Ochida" Journal bioorganic & medicinal chemistry
2 results on '"Atsuko Ochida"'

1. Identification of novel quinazolinedione derivatives as RORγt inverse agonist

Author

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, and Ayumu Sato

Subjects
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
Abstract

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.

Published
2018

2. Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives

Author

Junya Shirai, Yoshiyuki Fukase, Tetsuji Kawamoto, Mitsunori Kono, Tsuneo Oda, Mikio Shirasaki, Yasushi Fujitani, Hiroyuki Watanabe, Hideyuki Nakagawa, Keiko Uga, Michiko Tawada, Naohiro Taya, Akira Shibata, Takashi Imada, Yoshihide Tomata, Masashi Yamasaki, Tomoya Yukawa, Shoji Fukumoto, Hidekazu Tokuhara, Satoshi Yamamoto, Naoki Ishii, Atsuko Ochida, and Yoshihiro Banno

Subjects
Male, Models, Molecular, 0301 basic medicine, Injections, Intradermal, Stereochemistry, Carboxylic acid, Clinical Biochemistry, Retinoic acid, Administration, Oral, Pharmaceutical Science, Crystallography, X-Ray, Interleukin-23, 01 natural sciences, Biochemistry, Jurkat Cells, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, RAR-related orphan receptor gamma, Tetrahydroisoquinolines, Drug Discovery, Animals, Humans, Inverse agonist, Carboxylate, Molecular Biology, chemistry.chemical_classification, Mice, Inbred BALB C, Dose-Response Relationship, Drug, Molecular Structure, Bicyclic molecule, 010405 organic chemistry, Tetrahydroisoquinoline, Organic Chemistry, Nuclear Receptor Subfamily 1, Group F, Member 3, 0104 chemical sciences, 030104 developmental biology, chemistry, Models, Animal, Cytokines, Molecular Medicine, Derivative (chemistry)
Abstract

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.

Published
2018

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