A Randomized, Double Blind, Placebo and Active Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability and Potential Efficacy of a 12-Week Treatment With YM543 in Subjects With Type 2 Diabetes Mellitus

The purpose of this study is to investigate the safety of YM543 in type 2 Diabetes Mellitus patients and to investigate whether this study drug is effective in these patients

开始日期2007-02-01

申办/合作机构

Astellas Pharma, Inc.

100 项与 YM-543 相关的临床结果

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100 项与 YM-543 相关的转化医学

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100 项与 YM-543 相关的专利（医药）

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项与 YM-543 相关的文献（医药）

2017-04-01·Pharmaceutical Research3区 · 医学

Evaluation of the Utility of Chimeric Mice with Humanized Livers for the Characterization and Profiling of the Metabolites of a Selective Inhibitor (YM543) of the Sodium-Glucose Cotransporter 2

3区 · 医学

Article

作者: Nakada, Naoyuki

PURPOSEYM543 is a novel selective inhibitor of the sodium-glucose cotransporter 2. The objectives of the current study were to evaluate the utility of mice with humanized livers to predict human drug metabolites using YM543 as a case example.METHODSMetabolites of YM543 generated in humans and experimental animals including chimeric mice with humanized liver, PXB mice, were analyzed via liquid chromatography-mass spectrometry, liquid chromatography-radiometric detector or nuclear magnetic resonance spectrometer.RESULTSAfter oral administration of YM543, metabolites M1-M5 were detected in human plasma and urine. M2-M4 were detected in at least one species while M1 was not generated by experimental animals or in vitro systems. In the metabolite profiling in PXB mice, M1 was detected in both plasma and urine samples.CONCLUSIONSMetabolite profile of YM543 in PXB mice and humans was closely resemble. and the human specific metabolite was detected in the model mice. The human specific metabolite, M1, was difficult to know in advance to clinical study. The ability to predict the human metabolite profile including presence of human specific metabolites using PXB mice will likely facilitate development of new drug candidates for human use.

2013-08-01·Endocrine Research4区 · 医学

Pharmacological Characterization of YM543, a Newly Synthesized, Orally Active SGLT2 Selective Inhibitor

4区 · 医学

Article

作者: Imamura, Masakazu ; Yamajuku, Daisuke ; Noda, Atsushi ; Yokono, Masanori ; Kihara, Rumi ; Kurosaki, Eiji ; Shibasaki, Masayuki ; Tahara, Atsuo ; Kobayashi, Yoshinori ; Tomiyama, Hiroshi

BACKGROUND AND AIMSodium-glucose cotransporter (SGLT) 2 is a specifically expressed transporter in the kidney that plays an important role in renal glucose reabsorption, and its inhibition may present a novel therapeutic strategy for treating diabetes. Here, we pharmacologically characterized YM543, a newly synthesized SGLT2 selective inhibitor to test this theory.RESULTSIn vitro studies revealed that YM543 potently and selectively inhibited mouse and human SGLT2 activities at nanomolar ranges. In vivo single oral administration of YM543 dose-dependently and significantly reduced blood glucose levels and improved glucose tolerance with a concomitant increase in urinary glucose excretion in KK/A^y type 2 diabetic mice, effects that were sustained even after 12 h. Repeated once-daily oral administration of YM543 for 5 weeks significantly reduced hyperglycemia in type 2 diabetic mice. In addition, combination treatment of YM543 with rosiglitazone or metformin additively improved diabetic symptoms. In contrast, YM543 did not affect normoglycemia at pharmacological doses in normal mice.CONCLUSIONSResults from the present study suggest that YM543 is an orally active SGLT2 selective inhibitor which reduces hyperglycemia with a concomitant increase in urinary glucose excretion, indicating its promise as an effective treatment against type 2 diabetes.

2013-07-01·Bioorganic & Medicinal Chemistry3区 · 医学

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: Discovery of YM543

3区 · 医学

Article

作者: Keita Nakanishi ; Atsushi Noda ; Kazuhiro Kosakai ; Makoto Takeuchi ; Yasufumi Ohkura ; Kazuhiro Ikegai ; Masayuki Yokota ; Masakazu Imamura ; Takayuki Suzuki ; Yoshinori Kobayashi ; Mitsuaki Ohta ; Tomokazu Koide ; Hiroshi Tomiyama ; Eiji Kurosaki ; Takeshi Murakami

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.

100 项与 YM-543 相关的药物交易

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