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Your search keyword '"Ryoukichi Koyama"' showing total 3 results
Start Over Author "Ryoukichi Koyama" Topic chemistry.chemical_compound
3 results on '"Ryoukichi Koyama"'

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
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2. Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds

Author

Atsuko Ochida, Yoshihide Tomata, Wes Lane, Isaac Hoffman, Masaharu Nakayama, Hideyuki Nakagawa, Ayumu Sato, Tetsuji Kawamoto, Mitsunori Kono, Toshitake Okui, Shinichi Masada, Mikio Shirasaki, Masashi Yamasaki, Yasushi Fujitani, Akira Shibata, Keiko Uga, Junya Shirai, Yoshiyuki Fukase, Kazuko Yonemori, Ryoukichi Koyama, Bi-Ching Sang, Robert J. Skene, Keiko Koga, and Satoshi Yamamoto

Subjects
0301 basic medicine, Male, Models, Molecular, Clinical Biochemistry, Retinoic acid, Glycine, Pharmaceutical Science, Administration, Oral, Pharmacology, Crystallography, X-Ray, 01 natural sciences, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Jurkat Cells, Mice, Structure-Activity Relationship, RAR-related orphan receptor gamma, In vivo, Oral administration, Drug Discovery, Inverse agonist, Potency, Animals, Humans, Molecular Biology, Mice, Inbred BALB C, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Organic Chemistry, Nuclear Receptor Subfamily 1, Group F, Member 3, 0104 chemical sciences, 030104 developmental biology, chemistry, Nuclear receptor, Models, Animal, Molecular Medicine, Interleukin 17
Abstract

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

Published
2017

3. Parallel fluorescent probe synthesis based on the large-scale preparation of BODIPY FL propionic acid

Author

Noriyuki Nii, Nobuyuki Negoro, Shinkichi Suzuki, Ryoukichi Koyama, Taisuke Katoh, Masato Yoshikawa, Ryosuke Arai, Takatoshi Yogo, Yoshihide Tomata, and Takeshi Yamamoto

Subjects
Boron Compounds, Fluorophore, 010405 organic chemistry, Stereochemistry, Ligand, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, 010402 general chemistry, Ligands, 01 natural sciences, Biochemistry, Fluorescence, Combinatorial chemistry, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Receptors, Estrogen, Drug Discovery, Molecular Medicine, BODIPY, Propionates, Molecular Biology, Fluorescent Dyes
Abstract

We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but it is difficult to prepare a large amount of 1, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50=80nM), demonstrating the usefulness of Parallel-FPS.

Published
2016

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