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Your search keyword '"Miyahisa I"' showing total 2 results
Start Over Author "Miyahisa I" Topic oxadiazoles
2 results on '"Miyahisa I"'

1. Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents.

Author

Imamura K, Tomita N, Kawakita Y, Ito Y, Ono K, Nii N, Miyazaki T, Yonemori K, Tawada M, Sumi H, Satoh Y, Yamamoto Y, Miyahisa I, Sasaki M, Satomi Y, Hirayama M, Nishigaki R, and Maezaki H

Subjects
Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colonic Neoplasms drug therapy, Drug Evaluation, Preclinical, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, HCT116 Cells, Humans, Inhibitory Concentration 50, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver metabolism, Oxadiazoles pharmacokinetics, Oxadiazoles therapeutic use, Oxadiazoles toxicity, Piperidines chemistry, Piperidines metabolism, Piperidines pharmacology, Protein Binding, Pyridazines pharmacokinetics, Pyridazines therapeutic use, Pyridazines toxicity, Spiro Compounds chemistry, Stearoyl-CoA Desaturase metabolism, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemistry, Enzyme Inhibitors chemical synthesis, Oxadiazoles chemical synthesis, Pyridazines chemical synthesis, Stearoyl-CoA Desaturase antagonists & inhibitors
Abstract

A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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2. In vitro and in vivo antitumor activities of T-3764518, a novel and orally available small molecule stearoyl-CoA desaturase 1 inhibitor.

Author

Nishizawa S, Sumi H, Satoh Y, Yamamoto Y, Kitazawa S, Honda K, Araki H, Kakoi K, Imamura K, Sasaki M, Miyahisa I, Satomi Y, Nishigaki R, Hirayama M, Aoyama K, Maezaki H, and Hara T

Subjects
Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents metabolism, Apoptosis drug effects, Biological Availability, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Endoplasmic Reticulum Stress drug effects, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacokinetics, Fatty Acids metabolism, HCT116 Cells, Humans, Mice, Oxadiazoles administration & dosage, Oxadiazoles metabolism, Pyridazines administration & dosage, Pyridazines metabolism, Stearoyl-CoA Desaturase metabolism, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Oxadiazoles pharmacokinetics, Oxadiazoles pharmacology, Pyridazines pharmacokinetics, Pyridazines pharmacology, Stearoyl-CoA Desaturase antagonists & inhibitors, Xenograft Model Antitumor Assays
Abstract

Most cancer cells are characterized by elevated lipid biosynthesis. The rapid proliferation of cancer cells requires de novo synthesis of fatty acids. Stearoyl-CoA desaturase-1 (SCD1), a key enzyme for lipogenesis, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. Therefore, it has been studied as a candidate target for cancer therapy. In this study, we demonstrate the pharmacological properties of T-3764518, a novel and orally available small molecule inhibitor of SCD1. T-3764518 inhibited stearoyl-CoA desaturase-catalyzed conversion of stearoyl-CoA to oleoyl-CoA in colorectal cancer HCT-116 cells and their growth. Further, it slowed tumor growth in an HCT-116 and a mesothelioma MSTO-211H mouse xenograft model. Comprehensive lipidomic analyses revealed that T-3764518 increases the membrane ratio of saturated: unsaturated fatty acids in various lipid species such as phosphatidylcholines and diacylglycerols in both cultured cells and HCT-116 xenografts. Treatment-associated lipidomic changes were followed by activated endoplasmic reticulum (ER) stress responses such as increased immunoglobulin heavy chain-binding protein expression in HCT-116 cells. These T-3764518-induced changes led to an increase in cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptosis. Additionally, bovine serum albumin conjugated with oleic acid, an SCD1 product, prevented cell growth inhibition and ER stress responses by T-3764518, indicating that these outcomes were not attributable to off-target effects. These results indicate that T-3764518 is a promising new anticancer drug candidate., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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