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Your search keyword '"Okuno, Takayuki"' showing total 7 results
Start Over Author "Okuno, Takayuki" Publisher elsevier science ltd
7 results on '"Okuno, Takayuki"'

1. Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors.

Author

Hayashi K, Kondo N, Omori N, Yoshimoto R, Hato M, Shigaki S, Nagasawa A, Ito M, and Okuno T

Subjects
Animals, Benzimidazoles chemical synthesis, Benzimidazoles chemistry, Coenzyme A Ligases metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Mice, Mice, Knockout, Molecular Structure, Structure-Activity Relationship, Benzimidazoles pharmacology, Coenzyme A Ligases antagonists & inhibitors, Drug Discovery, Enzyme Inhibitors pharmacology
Abstract

Long-chain acyl-CoA synthetase-1 (ACSL1), an enzyme that catalyzes the synthesis of long-chain acyl-CoA from the corresponding fatty acids, is believed to play essential roles in lipid metabolism. Structure activity relationship studies based on HTS hit compound 1 delivered the benzimidazole series as the first selective and highly potent ACSL1 inhibitors. Representative compound 13 exhibited not only remarkable inhibitory activity against ACSL1 (IC 50  = 0.042 μM) but also excellent selectivity for the other ACSL isoforms. In addition, compound 13 demonstrated an in vivo suppression effect against the production of long-chain acyl-CoAs in mouse., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2021
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2. Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitor, S18-000003.

Author

Sasaki Y, Odan M, Yamamoto S, Kida S, Ueyama A, Shimizu M, Haruna T, Watanabe A, and Okuno T

Subjects
Administration, Oral, Amides pharmacokinetics, Amides therapeutic use, Animals, Autoimmune Diseases drug therapy, Binding Sites, Binding, Competitive, Crystallography, X-Ray, Drug Evaluation, Preclinical, Half-Life, Humans, Interleukin-17 metabolism, Interleukin-23 pharmacology, Mice, Molecular Dynamics Simulation, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Protein Binding, Rats, Skin drug effects, Skin metabolism, Structure-Activity Relationship, Th17 Cells cytology, Th17 Cells drug effects, Th17 Cells metabolism, Amides chemistry, Nuclear Receptor Subfamily 1, Group F, Member 3 antagonists & inhibitors
Abstract

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, ROR γ t 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 ROR γ t inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable ROR γ t inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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3. Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy.

Author

Nishiura Y, Matsumura A, Kobayashi N, Shimazaki A, Sakamoto S, Kitade N, Tonomura Y, Ino A, and Okuno T

Subjects
Acetyl-CoA Carboxylase metabolism, Alkenes chemical synthesis, Alkenes chemistry, Animals, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Mice, Mice, Inbred C57BL, Molecular Structure, Structure-Activity Relationship, Acetyl-CoA Carboxylase antagonists & inhibitors, Alkenes pharmacology, Drug Discovery, Enzyme Inhibitors pharmacology
Abstract

Novel acetyl-CoA carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compound 1b improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2e which showed in vivo efficacy in C57BL/6 mice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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4. Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile.

Author

Tamura Y, Hayashi K, Omori N, Nishiura Y, Watanabe K, Tanaka N, Fujioka M, Kouyama N, Yukimasa A, Tanaka Y, Chiba T, Tanioka H, Nambu H, Yukioka H, Sato H, and Okuno T

Subjects
Administration, Oral, Animals, Anti-Obesity Agents pharmacokinetics, Anti-Obesity Agents therapeutic use, Benzimidazoles pharmacokinetics, Benzimidazoles pharmacology, Benzimidazoles therapeutic use, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System metabolism, Half-Life, Mice, Obesity drug therapy, Rats, Receptors, Neuropeptide Y metabolism, Structure-Activity Relationship, Sulfones pharmacology, Sulfones therapeutic use, Weight Gain drug effects, Anti-Obesity Agents chemistry, Benzimidazoles chemistry, Receptors, Neuropeptide Y agonists, Sulfones chemistry
Abstract

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2013
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5. Identification of a novel and orally available benzimidazole derivative as an NPY Y5 receptor antagonist with in vivo efficacy.

Author

Tamura Y, Omori N, Kouyama N, Nishiura Y, Hayashi K, Watanabe K, Tanaka Y, Chiba T, Yukioka H, Sato H, and Okuno T

Subjects
Administration, Oral, Animals, Drug Design, Drug Stability, Humans, Inhibitory Concentration 50, Mice, Mice, Obese, Protein Binding drug effects, Solubility, Structure-Activity Relationship, Benzimidazoles chemistry, Benzimidazoles pharmacology, Receptors, Neuropeptide Y antagonists & inhibitors
Abstract

Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile leading to in vivo efficacy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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6. Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles.

Author

Tamura Y, Omori N, Kouyama N, Nishiura Y, Hayashi K, Watanabe K, Tanaka Y, Chiba T, Yukioka H, Sato H, and Okuno T

Subjects
Animals, Benzimidazoles chemical synthesis, Benzimidazoles metabolism, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System metabolism, Drug Design, Humans, Mice, Microsomes, Liver metabolism, Obesity drug therapy, Pyridones chemical synthesis, Pyridones metabolism, Rats, Receptors, Neuropeptide Y metabolism, Benzimidazoles chemistry, Benzimidazoles pharmacology, Pyridones chemistry, Pyridones pharmacology, Receptors, Neuropeptide Y antagonists & inhibitors
Abstract

Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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7. Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist.

Author

Omori N, Kouyama N, Yukimasa A, Watanabe K, Yokota Y, Tanioka H, Nambu H, Yukioka H, Sato N, Tanaka Y, Sekiguchi K, and Okuno T

Subjects
Animals, Anti-Obesity Agents pharmacokinetics, Anti-Obesity Agents pharmacology, Benzoxazoles pharmacokinetics, Benzoxazoles pharmacology, Body Weight drug effects, Eating drug effects, Humans, Mice, Obesity metabolism, Rats, Receptors, Neuropeptide Y metabolism, Structure-Activity Relationship, Anti-Obesity Agents chemistry, Anti-Obesity Agents therapeutic use, Benzoxazoles chemistry, Benzoxazoles therapeutic use, Obesity drug therapy, Receptors, Neuropeptide Y antagonists & inhibitors
Abstract

We report a hit to lead study on a novel benzoxazole NPY Y5 antagonist. Starting from HTS hit 1, structure-activity relationships were developed. Compound 12 showed reduction of food intake and a tendency to suppress body weight gain over the 21-day experimental period., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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