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Your search keyword '"Yoshimitsu Naoe"' showing total 11 results
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11 results on '"Yoshimitsu Naoe"'

1. Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists

Author

Carsten T. Beuckmann, Yuji Kazuta, Osamu Takenaka, Fumihiro Ozaki, Yu Yoshida, Ikuo Kushida, Makoto Nakagawa, Michiyuki Suzuki, Masahiro Yonaga, Takashi Ueno, Yoshimitsu Naoe, and Taro Terauchi

Subjects
Cyclopropanes, Male, Models, Molecular, Clinical Biochemistry, Pharmaceutical Science, Pharmacology, Biochemistry, Sleep measurement, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Orexin Receptors, Sleep Initiation and Maintenance Disorders, mental disorders, Drug Discovery, Animals, Humans, Receptor, Molecular Biology, Orexin Receptor Antagonists, Aryl, digestive, oral, and skin physiology, Organic Chemistry, In vitro, Orexin, Mice, Inbred C57BL, Orally active, nervous system, chemistry, Design synthesis, Drug Design, Molecular Medicine, Sleep, hormones, hormone substitutes, and hormone antagonists, psychological phenomena and processes
Abstract

Herein we describe the design, synthesis, and structure–activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33b ((−)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33b may serve as a valuable template for the development of new orexin receptor antagonists.

Published
2014

2. Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist

Author

Michiyuki Suzuki, Takashi Doko, Keiichi Sorimachi, Toshiaki Tanaka, Carsten T. Beuckmann, Yoshimitsu Naoe, Masahiro Yonaga, Yu Yoshida, Taro Terauchi, Shunsuke Ozaki, Takemura Ayumi, Takashi Ueno, and Fumihiro Ozaki

Subjects
Cyclopropanes, Male, Models, Molecular, medicine.medical_specialty, Lemborexant, Administration, Oral, Aminopyridines, Pharmacology, Mice, Structure-Activity Relationship, Orexin Receptors, Internal medicine, mental disorders, Drug Discovery, medicine, Structure–activity relationship, Animals, Humans, Receptor, Cells, Cultured, Molecular Structure, Chemistry, Drug discovery, digestive, oral, and skin physiology, Antagonist, Amides, Orexin receptor, Orexin, Mice, Inbred C57BL, Endocrinology, Pyrimidines, nervous system, Drug Design, Microsomes, Liver, Molecular Medicine, Calcium, Orexin Receptor Antagonists, Orexin antagonist, psychological phenomena and processes
Abstract

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

Published
2015

3. pH Dependent cycloaromatization of enediyne model compounds via γ-oxo ketene acetal intermediates

Author

Ichiro Suzuki, Hisao Nemoto, Masayuki Shibuya, Yoshimitsu Naoe, and Masahiko Bando

Subjects
chemistry.chemical_compound, chemistry, Stereochemistry, Organic Chemistry, Drug Discovery, Acetal, Enediyne, Ph dependent, Ketene, Biochemistry
Abstract

The Myers-Saito-type cyclizations of enediyne derivatives via γ-oxo ketene acetal intermediates generated by the neighboring group participation of naphthoate ester groups in acidic media are described.

Published
1998

4. Cycloaromatization of enediyne model compounds via a reaction cascade triggered by hydrolysis of the α-alkynylmalonates

Author

Katsuya Ishigaki, Tadaaki Kawakami, Yoshimitsu Naoe, Yoshimitsu Nagao, Masakazu Wakayama, Masayuki Shibuya, Hisashi Shimizu, and Hisao Nemoto

Subjects
Quenching (fluorescence), Chemistry, Stereochemistry, Organic Chemistry, Disproportionation, Ester hydrolysis, Photochemistry, Biochemistry, Toluene, Hydrolysis, chemistry.chemical_compound, Deuterium, Cascade, Drug Discovery, Enediyne
Abstract

Diethyl α-methoxy-α-alkynylmalotate derivatives of cis -enediynes were synthesized and they produced toluenebiradicals via the reaction cascade triggered by ester hydrolysis. Deuterium labeling studies suggested that the reaction involved the self quenching process by fairly fast disproportionation of toluene biradicals producing zwitterionic species.

Published
1996

5. pH dependent cycloaromatization of enediyne model compounds via enyne-allene intermediates

Author

Hisao Nemoto, Katsuya Ishigaki, Junya Kikuishi, Masayuki Shibuya, H. Iitsuka, and Yoshimitsu Naoe

Subjects
chemistry.chemical_compound, chemistry, Enyne, Stereochemistry, Allene, Organic Chemistry, Drug Discovery, Hydroxy group, Enediyne, Ph dependent, Biochemistry
Abstract

Cis -enediyne derivatives 1 underwent Myers-type Cycloaromatization under acidic conditions via the enyne-allene intermediate 2 by the triggering action of the hydroxy group. Compound 1 showed pH dependent DNA-cleaving activity.

Published
1995

6. ChemInform Abstract: A Convenient Synthesis of Acyclic Conjugated Enediynes

Author

Yoshimitsu Naoe, Yasuhiro Sakai, and Masayuki Shibuya

Subjects
chemistry.chemical_compound, Chemistry, Hydroxy group, General Medicine, Conjugated system, Combinatorial chemistry
Abstract

Novel synthetic method for acyclic cis -hex-3-ene-1,5-diyne derivatives via elimination of tert -hydroxy group has been described.

Published
2010

7. ChemInform Abstract: pH-Dependent Cycloaromatization of Enediyne Model Compounds via Enyne- Allene Intermediates

Author

Katsuya Ishigaki, Hisao Nemoto, Yoshimitsu Naoe, Masayuki Shibuya, H. Iitsuka, and Junya Kikuishi

Subjects
chemistry.chemical_compound, Enyne, Chemistry, Stereochemistry, Allene, Hydroxy group, Enediyne, Ph dependent, General Medicine
Abstract

Cis -enediyne derivatives 1 underwent Myers-type Cycloaromatization under acidic conditions via the enyne-allene intermediate 2 by the triggering action of the hydroxy group. Compound 1 showed pH dependent DNA-cleaving activity.

Published
2010

8. ChemInform Abstract: Cycloaromatization of Enediyne Model Compounds via a Reaction Cascade Triggered by Hydrolysis of the α-Alkynylmalonates

Author

Masayuki Shibuya, Hisashi Shimizu, Katsuya Ishigaki, Yoshimitsu Nagao, Masakazu Wakayama, Hisao Nemoto, Tadaaki Kawakami, and Yoshimitsu Naoe

Subjects
Hydrolysis, chemistry.chemical_compound, Quenching (fluorescence), Deuterium, Chemistry, Cascade, Enediyne, Disproportionation, Ester hydrolysis, General Medicine, Photochemistry, Toluene
Abstract

Diethyl α-methoxy-α-alkynylmalotate derivatives of cis -enediynes were synthesized and they produced toluenebiradicals via the reaction cascade triggered by ester hydrolysis. Deuterium labeling studies suggested that the reaction involved the self quenching process by fairly fast disproportionation of toluene biradicals producing zwitterionic species.

Published
2010

9. Corrigendum to 'Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists' [Bioorg. Med. Chem. 22 (2014) 6071–6088]

Author

Michiyuki Suzuki, Yu Yoshida, Yoshimitsu Naoe, Taro Terauchi, Takashi Ueno, Yuji Kazuta, Fumihiro Ozaki, Ikuo Kushida, Osamu Takenaka, Makoto Nakagawa, Carsten T. Beuckmann, and Masahiro Yonaga

Subjects
Stereochemistry, Chemistry, Orexin Receptor Antagonists, Aryl, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, chemistry.chemical_compound, Orally active, Design synthesis, Drug Discovery, Molecular Medicine, Molecular Biology
Published
2015

10. Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006):A Potent and Efficacious Oral Orexin Receptor Antagonist.

Author

Yu Yoshida, Yoshimitsu Naoe, Taro Terauchi, Fumihiro Ozaki, Takashi Doko, Ayumi Takemura, Toshiaki Tanaka, Keiichi Sorimachi, CarstenT. Beuckmann, Michiyuki Suzuki, Takashi Ueno, Shunsuke Ozaki, and Masahiro Yonaga

Subjects
*DRUG development, *CARBOXAMIDES, *DRUG efficacy, *ORAL medication, *OREXINS, *DRUG receptors
Abstract

The orexin/hypocretin receptors area family of G protein-coupledreceptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughoutthe central nervous system and are involved in the regulation of thesleep/wake cycle. Because modulation of these receptors constitutesa promising target for novel treatments of disorders associated withthe control of sleep and wakefulness, such as insomnia, the developmentof orexin receptor antagonists has emerged as an important focus indrug discovery research. Here, we report the design, synthesis, characterization,and structure–activity relationships (SARs) of novel orexinreceptor antagonists. Various modifications made to the core structureof a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemicaland pharmacological profiles. The investigation afforded a potentialtherapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006),an orally active, potent orexin antagonist. The efficacy was demonstratedin mice in an in vivo study by using sleep parameter measurements. [ABSTRACT FROM AUTHOR]

Published
2015
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11. A convenient synthesis of acyclic conjugated enediynes

Author

Yoshimitsu Naoe, Yasuhiro Sakai, and Masayuki Shibuya

Subjects
chemistry.chemical_compound, Chemistry, Stereochemistry, Organic Chemistry, Drug Discovery, Hydroxy group, Conjugated system, Biochemistry, Combinatorial chemistry
Abstract

Novel synthetic method for acyclic cis -hex-3-ene-1,5-diyne derivatives via elimination of tert -hydroxy group has been described.

Published
1995

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