Faculty Profiles - KAKUTA Hiroki

Other Link： http://search.jamas.or.jp/link/ui/2016224078

アレルギー性気道炎症マウスモデルにおけるレチノイドX受容体(RXR)パーシャルアゴニストの治療効果に関する研究

藤井詩子, 金廣有彦, 谷口暁彦, 森近大介, 小田尚廣, 栗本悦子, 古賀光, 早稲田公一, 加来田博貴, 宮原信明, 木浦勝行, 谷本光音

日本呼吸器学会誌 5 ( 増刊 ) 178 - 178 2016.3

iPSC-derived cancer stem cells provide a model of tumor vasculature Reviewed International journal

Hiroki Kakuta

American journal of cancer research 6 ( 9 ) 1906 - 1921 2016

Language：English Publisher：E-CENTURY PUBLISHING CORP

To grow beyond a size of approximately 1-2 mm(3), tumor cells activate many processes to develop blood vasculature. Growing evidences indicate that the formation of the tumor vascular network is very complex, and is not restricted to angiogenesis. Cancer cell-derived tumor vasculatures have been recently described. Among them, endothelial differentiation of tumor cells have been directly related to cancer stem cells, which are cells within a tumor that possess the capacity to self-renew, and to exhibit multipotential heterogeneous lineages of cancer cells. Vasculogenic mimicry has been described to be formed by cancer cells expressing stemness markers. Thus, cancer stem cells have been proposed to contribute to vasculogenic mimicry, though its relation is yet to be clarified. Here, we analyzed the tumor vasculature by using a model of mouse cancer stem cells, miPS-LLCcm cells, which we have previously established from mouse induced pluripotent stem cells and we introduced the DsRed gene in miPS-LLCcm to trace them in vivo. Various features of vasculature were evaluated in ovo, in vitro, and in vivo. The tumors formed in allograft nude mice exhibited angiogenesis in chick chorioallantoic membrane assay. In those tumors, along with penetrated host endothelial vessels, we detected endothelial differentiation from cancer stem cells and formation of vasculogenic mimicry. The angiogenic factors such as VEGF-A and FGF2 were expressed predominantly in the cancer stem cells subpopulation of miPS-LLCcm cells. Our results suggested that cancer stem cells play key roles in not only the recruitment of host endothelial vessels into tumor, but also in maturation of endothelial linage of cancer stem cell's progenies. Furthermore, the undifferentiated subpopulation of the miPS-LLCcm participates directly in the vasculogenic mimicry formation. Collectively, we show that miPS-LLCcm cells have advantages to further study tumor vasculature and to develop novel targeting strategies in the future.

生細胞内のアスコルビン酸濃度分布のイメージング化に関する試み

田井章博, 石股直, 加来田博貴

ビタミン 89 ( 12 ) 595 - 596 2015.12

関節軟骨造影剤を用いた関節軟骨プロテオグリカンの評価

大橋俊孝, 加来田博貴, 芳谷学, 山田翔也, 大月孝志, 廣畑聡, 二宮善文, 西田圭一郎

日本結合組織学会学術大会プログラム・抄録集 47回 97 - 97 2015.5

レチノイドX受容体を標的とした創薬に関する研究

加来田博貴

ビタミン 89 ( 4 ) 177 - 178 2015.4

新規RXRパーシャルアゴニストCBt-PMNの炎症性腸疾患モデルにおける有効性の検討

滝澤慧, 古澤之裕, 古沢優貴, 小林俊貴, 山田翔也, 加来田博貴, 長谷耕二

日本薬学会年会要旨集 135年会 ( 3 ) 97 - 97 2015.3

RXR partial agonist NEt-4IB exerts therapeutic effects on inflammatory bowel disease without the side effects of RXR full agonists

Yuki Furusawa, Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Shoya Yamada, Makoto Makishima, Akihiro Tai, Hiroki Kakuta

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 248 2014.8

Elucidation of the pharmacokinetic difference of regioisomeric retinoid X receptor agonists having an alkoxy group by PET imaging

Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Yuki Furusawa, Shoya Yamada, Hiroyuki Hirano, Fumiaki Takenaka, Masaru Akehi, Takanori Sasaki, Eiji Matsuura, Akihiro Tai, Hiroki Kakuta

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 248 2014.8

Development of fluorescent retinoid X receptor ligands and Forster resonance energy transfer (FRET)-based RXR ligand screening method

Shoya Yamada, Mariko Nakayama, Kazutaka Kohara, Makoto Makishima, Hirotaka Naitou, Hiroki Kakuta

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 248 2014.8

新規X線造影剤による変形性膝関節症ラット関節軟骨の高解像度マイクロCT造影

大橋俊孝, 加来田博貴, 芳谷学, 大月孝志, 大野充昭, 山田翔也, 前原亜美, 廣畑聡, 西田圭一郎, 窪木拓男, 二宮善文

日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集 46回・61回 106 - 106 2014.6

PETイメージングを用いたアルコキシ基を有するレチノイドX受容体アゴニストの体内動態解析

加来田博貴, 小林俊貴, 古沢優貴, 山田翔也, 竹中文章, 明日卓, 佐々木崇了, 松浦栄次, 田井章博

ビタミン 88 ( 4 ) 213 - 213 2014.4

アルコキシ基を有するレチノイドX受容体アゴニストの位置異性体間における体内動態差の解明とその応用

小林俊貴, 古沢優貴, 山田翔也, 平野裕之, 竹中文章, 明日卓, 佐々木崇了, 松浦栄次, 田井章博, 加来田博貴

日本薬学会年会要旨集 134年会 ( 4 ) 81 - 81 2014.3

高精度第一原理計算およびMDシミュレーションを用いた核内受容体AF2インターフェースの動的構造解析

丸藤友彦, 石坪江梨花, 加来田博貴, 山田幸子, 槇島誠, 常盤広明

日本薬学会年会要旨集 134年会 ( 2 ) 81 - 81 2014.3

Retinoid X receptor ligands: a patent review (2007 - 2013) Reviewed

Hiroki Kakuta

Expert opinion on therapeutic patents 24 ( 4 ) 443 - 452 2014

Language：English Publisher：TAYLOR & FRANCIS LTD

Introduction: Retinoid X receptors (RXRs) are nuclear receptors that act as ligand-dependent transcription factors. RXRs function as homodimers or as heterodimers with other nuclear receptors, such as retinoic acid receptors, PPARs, liver X receptors, farnesoid X receptor, vitamin D receptor or thyroid hormone receptors. RXR ligands (agonists or antagonists) show various physiological effects, depending on their partner receptors. RXR agonist bexarotene (Targretin (R)) is used for the treatment of cutaneous T-cell lymphoma in clinical practice. RXR agonists were also reported to be useful for treatment of type 2 diabetes, autoimmune disease and Alzheimer's disease. RXR antagonists were also reported to be effective in type 2 diabetes treatment.
Areas covered: Here patent applications (2007 - 2013) concerning RXR ligands are summarized, and the usefulness of RXR ligands as pharmaceutical agents is discussed.
Expert opinion: RXR agonists show a wide variety of biological effects. However, they cause serious side effects, such as blood triglyceride elevation, hypothyroidism and others. Thus, for clinical application of RXR agonists, abrogation of these side effects is required. RXR heterodimer-selective agonists and RXR partial agonists exhibiting desired effects without side effects are expected to find clinical application.

DOI： 10.1517/13543776.2014.880692

リジンオリゴマーからなる関節軟骨特異的X線プローブの創出

大橋俊孝, 芳谷学, 大野充昭, 山田翔也, 大月孝志, 前原亜美, 廣畑聡, 西田圭一郎, 窪木拓男, 加来田博貴, 二宮善文

日本軟骨代謝学会プログラム・抄録集 27th 2014

Structurally simple cartilage probes constructed with epsilon-lysine oligomers targeting chondroitin sulfates

Hiroki Kakuta, Manabu Hagaya, Shoya Yamada, Fuminori Ohsawa, Ami Maehara, Aki Yoshida, Mitsuaki Ono, Ryuichi Nakahara, Keiichiro Nishida, Toshitaka Oohashi

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 246 2013.9

Development of fluorescent retinoid X receptor ligands as a ligand screening tool

Shoya Yamada, Mariko Nakayama, Makoto Makishima, Hirotaka Naitou, Hiroki Kakuta

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 246 2013.9

レチノイドX受容体パーシャルアゴニストNEt-4IBの創出と薬効・副作用評価

加来田博貴, 川田浩平, 中山真理子, 山田翔也, 小林俊貴, 古沢優貴, 大橋俊孝, 田井章博, 矢間太

ビタミン 87 ( 4 ) 254 - 254 2013.4

レチノイドX受容体を標的とするリガンド探索ツールとしての蛍光性リガンドの開発研究

山田翔也, 小原一剛, 中山真理子, 槙島誠, 内藤博敬, 加来田博貴

日本薬学会年会要旨集 133年会 ( 2 ) 70 - 70 2013.3

Discovery and application of a fluorescent RXR antagonist to fluorescence polarization assay

Shoya Yamada, Mariko Nakayama, Fuminori Ohsawa, Makoto Makishima, Hirotaka Naitou, Hiroki Kakuta

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 244 2012.8

Discovery of a novel benzotriazole-type retinoid X receptor partial-agonist decreasing plasma glucose level in type-2 diabetes mellitus with decreased side effects

Hiroki Kakuta, Nobumasa Yakushiji, Fuminori Ohsawa, Shoya Yamada, Mariko Nakayama, Kohei Kawata, Yui Ohta, Chisa Fujiwara, Toshitaka Oohashi, Makoto Makishima, Akihiro Tai, Hiroyuki Yasui, Yutaka Yoshikawa

CANCER RESEARCH 72 2012.4

新規RXRアゴニスト及びその類縁化合物のヒト肝における代謝特性の予測

合葉哲也, 村上由樹, 清水康正, 川田浩平, 中山真理子, 小笠原明美, 岡田淳芳, 黒崎勇二, 加来田博貴

日本薬学会年会要旨集 132年会 ( 2 ) 269 - 269 2012.3

関節軟骨に特異的に結合するX線造影化イメージングプローブの創出研究

芳谷学, 大澤史宜, 加来田博貴, 大橋俊孝

日本薬学会年会要旨集 132年会 ( 2 ) 271 - 271 2012.3

チアゾリジンジオン誘導体GPU-4の網膜血管新生抑制作用

中村信介, 林慧, 瀧澤悠加, 村瀬哲司, 鶴間一寛, 嶋澤雅光, 加来田博貴, 永澤秀子, 原英彰

日本薬理学雑誌 139 ( 3 ) 27P - 27P 2012.3

RXRアゴニストCBt-PMNのパーシャルアゴニスト活性発現機構の解明

大澤史宜, 薬師寺信匡, 篠崎亮介, 山田翔也, 中山真理子, 川田浩平, 槇島誠, 加来田博貴

日本薬学会年会要旨集 132年会 ( 2 ) 165 - 165 2012.3

蛍光性RXRリガンドの創出とRXRリガンド探索への応用

山田翔也, 中山真理子, 大田由衣, 槇島誠, 内藤博敬, 加来田博貴

日本薬学会年会要旨集 132年会 ( 2 ) 166 - 166 2012.3

RXRパーシャルアゴニストの創出ならびに乾癬モデルマウスでの有効性・副作用発現の評価

川田浩平, 中山真理子, 森下健一, 大澤史宜, 山田翔也, 大田由衣, 加来田博貴

日本薬学会年会要旨集 132年会 ( 2 ) 269 - 269 2012.3

メントン由来の二環性骨格を有する9-cis-レチノイン酸誘導体型RXRアゴニストの創製

沖津貴志, 山田翔也, 加来田博貴, 和田昭盛

メディシナルケミストリーシンポジウム講演要旨集 30th 2012

糖尿病治療に挑む新しい薬剤開発「教育・臨床現場の声」と「天然物・有機・無機化合物」からのアプローチレチノイドX受容体を標的に単剤1型・2型糖尿病治療薬候補化合物創製に挑む

加来田博貴

薬学雑誌 131 ( 6 ) 917 - 923 2011.6

Language：Japanese Publisher：(公社)日本薬学会

著者等は1型・2型糖尿病を問わず有用な化合物創出を目的に、レチノイドX受容体(RXR)に注目して研究を行っている。RXRは自身のホモダイマー、もしくはPPAR(ペルオキシソーム増殖因子活性化受容体)、LXR(肝臓X受容体)などとヘテロダイマーを形成して機能する。各種アルコキシ基を有するRXRアゴニストのRXR活性化能、更に同程度のRXR活性を有する化合物のPPAR/RXRおよびLXR/RXR活性について概説した。

DOI： 10.1248/yakushi.131.917

有機合成化学の若い力創造への挑戦リバイバル創薬

加来田博貴

日本薬学会年会要旨集 131年会 ( 1 ) 160 - 160 2011.3

Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors

Ryosuke Fukai, Xiaoxia Zheng, Kazunori Motoshima, Hiroki Kakuta

Yakugaku Zasshi 131 ( 3 ) 347 - 351 2011.3

Language：Japanese Publishing type：Book review, literature introduction, etc. Publisher：(公社)日本薬学会

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturbance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4- trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N- (substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3- trifluoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine. © 2011 The Pharmaceutical Society of Japan.

DOI： 10.1248/yakushi.131.347

Scopus

炎症性サイトカインを用いた腸疾患のイメージングと治療薬薬効評価法の検討

赤田直輝, 東川桂, 八木克治, 渡辺恵子, 加来田博貴, 廣村信, 榎本秀一

日本薬学会年会要旨集 131年会 ( 3 ) 188 - 188 2011.3

[Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors] Reviewed

Hiroki Kakuta

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 131 ( 3 ) 347 - 351 2011

Language：Japanese Publisher：PHARMACEUTICAL SOC JAPAN

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturbance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl) -4-trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N- (substituted) benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl) benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine.

DOI： 10.1248/yakushi.131.347

[Challenge of creating single-agents for the treatment of type 1 and 2 diabetes by targeting retinoid X receptor] Reviewed

Hiroki Kakuta

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 131 ( 6 ) 917 - 923 2011

Language：Japanese Publisher：PHARMACEUTICAL SOC JAPAN

It might be seen as reckless to challenge to create single-agents for the treatment of both type I diabetes caused by the destruction of the Langerhans,3 cells in pancreas by excessive autoimmunity, and type 2 diabetes caused by the obesity. However, we hypothesized that retinoid X receptor (RXR) agonists, which are researched for the treatment of type 2 diabetes, will also be useful like metformin, which shows insulin-sparing effect in type 1 diabetes. This is because PPAR gamma/RXR is known to be a target of thiazolidinediones (TZDs), which are used for the treatment of insulin resistance, LXR/RXR is reported to be involved in glucose/lipid metabolism, and these heterodimers can be activated by RXR agonists alone (permissive mechanism). However, repeated administration of RXR agonists can elevate blood triglyceride and induce hypothyroidism. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl- (3-isopropoxy-4-isopropylphenyl)amino] nicotinic acid: NEt-3IP) and evaluated the RXR-, PPAR/RXR- and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analog (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analog (51) and n-propoxy analog (5k), but exhibited more potent PPAR/RXR-agonistic activity than 51 or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected to be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia.

DOI： 10.1248/yakushi.131.917

医薬化学インスリンに頼らず血糖値を下げる肝臓選択的グルコキナーゼ活性化剤

Tchreg細胞株(HOZOT)における核内受容体RXRαとPPARγの発現、細胞内局在並びに機能解析(Expression kinetics, subcellular localization, and functional properties of RXRα and PPARγ in Tchreg (cytotoxic, helper, and regulatory T) cell line, HOZOT)

鈴木基之, 山崎史行, 加来田博貴

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 83回・33回 1P - 0364 2010.12

シクロオキシゲナーゼ1(COX‐1)阻害を基盤としたベンズアニリド骨格を有する新規鎮痛剤の創製

深井良祐, ZHENG Xiaoxio, 本島和典, 田井章博, 矢間太, 加来田博貴

メディシナルケミストリーシンポジウム講演要旨集 29th 144 - 145 2010.10

加来田博貴

ファルマシア 46 ( 6 ) 559 - 560 2010.6

新規骨格を有するRXRアゴニストの体内動態に関する基礎的検討

村上由樹, 小笠原明美, 大澤史宜, 合葉哲也, 川崎博己, 加来田博貴, 黒崎勇二

日本薬学会年会要旨集 130年会 ( 4 ) 265 - 265 2010.3

核内受容体RXRアゴニストのマウス鼻アレルギーモデルに対する効果について

杉山茉由, 山本篤毅, 篠崎亮介, 日下絵梨子, 妹尾訓枝, 宮地弘幸, 加来田博貴, 杉本幸雄

日本薬理学雑誌 135 ( 3 ) 21P - 21P 2010.3

NOの被観血的、非侵襲的な定量法の開発とアレルギーモデルでの検証

高島征助, 妹尾訓枝, 山本篤毅, 杉本幸雄, 加来田博貴

日本薬学会年会要旨集 130年会 ( 3 ) 138 - 138 2010.3

新規低脂溶性RARβ選択的アゴニストの創製研究

大澤史宜, 山田翔也, 山本篤毅, 深井良祐, 鄭霞暁, 槇島誠, 杉本幸雄, 田井章博, 加来田博貴

日本薬学会年会要旨集 130年会 ( 2 ) 243 - 243 2010.3

脂溶性低減を志向したカルボン酸等価体を有する新規RXRアゴニストの創製研究

藤井周司, 大澤史宜, 深井良祐, 山田翔也, 槇島誠, 加来田博貴

日本薬学会年会要旨集 130年会 ( 2 ) 243 - 243 2010.3

炎症性サイトカインを標的とする潰瘍性大腸炎診断プローブの探索

東川桂, 八木克治, 渡辺恵子, 加来田博貴, 金山洋介, 廣村信, 榎本秀一

日本薬学会年会要旨集 130年会 ( 4 ) 125 - 125 2010.3

次世代の創薬研究を担う若手研究者のチカラ大学におけるメディシナルケミストリーシクロオキシゲナーゼ-1(COX-1)阻害剤の開発意義とその創出

深井良祐, 鄭暁霞, 本島和典, 加来田博貴

日本薬学会年会要旨集 130年会 ( 1 ) 394 - 394 2010.3

Pioglitazoneの抗炎症作用における作用機序に関する研究

山本篤毅, 杉山茉由, 妹尾訓枝, 日下絵梨子, 篠崎亮介, 加来田博貴, 杉本幸雄

日本薬理学雑誌 135 ( 3 ) 21P - 21P 2010.3

糖尿病治療に挑む新しい薬剤開発「教育・臨床現場の声」と「天然物・有機・無機化合物」からのアプローチレチノイドX受容体を標的に単剤1型2型糖尿病治療薬候補化合物創製に挑む

加来田博貴

日本薬学会年会要旨集 130年会 ( 1 ) 221 - 221 2010.3

カラゲニン浮腫試験に対するRXRアゴニストNEt-3IPの効果

山本篤毅, 杉山茉由, 篠崎亮介, 宮地弘幸, 加来田博貴, 杉本幸雄

日本薬理学雑誌 134 ( 4 ) 11P - 11P 2009.10

核内受容体RXRアゴニストの抗アレルギー作用について

杉山茉由, 山本篤毅, 篠崎亮介, 宮地弘幸, 加来田博貴, 杉本幸雄

日本薬理学雑誌 134 ( 4 ) 10P - 10P 2009.10

Design and in vitro/in vivo evaluation of novel Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy4-isopropylphenylamino Moiety, NEt-3IP.

Hiroki Kakuta, Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Ken-ichi Morishita, Makoto Makishima, Shigeyuki Uno, Yukio Sugimoto

CANCER RESEARCH 69 2009.5

新規レチノイドX受容体アゴニストNEt-3IPのラットにおける体内動態評価

小笠原明美, 薬師寺信匡, 合葉哲也, 川崎博己, 黒崎勇二, 加来田博貴

日本薬学会年会要旨集 129年会 ( 4 ) 220 - 220 2009.3

RXRアゴニストNEt-3IPの抗アレルギー作用について

加来田博貴, 久山翔司, 尾崎友美, 杉山茉由, 宇野茂之, 槇島誠, 森下健一, 鄭暁霞, 原田隼, 杉本幸雄

日本薬学会年会要旨集 129年会 ( 2 ) 114 - 114 2009.3

チアゾリジンジオン骨格を有する新規選択的血管新生阻害剤GPU-4の開発

林慧, 三原法秀, 岡部泰之, 上田聡, 奥田健介, 加来田博貴, 松永望, 原英彰, 永澤秀子

日本薬学会年会要旨集 129年会 ( 2 ) 114 - 114 2009.3

カラゲニン浮腫試験に対するRXRアゴニストNEt-3IPの効果

山本篤毅, 杉山茉由, 篠崎亮介, 宮地弘幸, 加来田博貴, 杉本幸雄

日本薬理学会近畿部会プログラム・要旨集 115th 2009

RXRアゴニストNEt-3IPの樹状細胞分化抑制・制御性T細胞誘導能と抗アレルギー作用

加来田博貴, 大澤史宜, 杉山茉由, 杉本幸雄, 槇島誠, 鈴木基之, 中村修治

メディシナルケミストリーシンポジウム講演要旨集 28th 2009

抗がん・抗炎症・抗アレルギー剤を指向した低脂溶性レキシノイド (特集バイオ応用技術の最前線)

加来田博貴

ケミカルエンジニヤリング 53 ( 11 ) 855 - 860 2008.11

シクロオキシゲナーゼ1阻害剤は胃潰瘍形成のない魅力的な抗がん剤候補である。ベンズアミドタイプのCOX-1阻害剤による提示。(COX-1-selective inhibitors are attractive candidates for anti-cancer agents that do not cause gastric damage)

加来田博貴, 鄭曉霞, 小田博之, 原田隼, 杉本幸雄, 永澤秀子, 佐々木健二, 田井章博

日本癌学会総会記事 67回 369 - 369 2008.9

強い新規血管新生阻害作用を有するチアゾリジンジオン誘導体の分子設計、合成及び生物活性評価(Design, synthesis, and biological evaluation of potent anti-angiogenic thiazolidinedione derivatives)

永澤秀子, 林慧, 岡部泰之, 上田聡, 加来田博貴

日本癌学会総会記事 67回 306 - 306 2008.9

環状イミド構造を有する新規血管新生阻害剤の分子設計

林慧, 岡部泰之, 須藤智美, 三原法秀, 上田聡, 加来田博貴, 永澤秀子

日本薬学会年会要旨集 128年会 ( 2 ) 52 - 52 2008.3

新規シクロオキシゲナーゼ1(COX-1)阻害剤の開発とその胃潰瘍形成の有無および鎮痛効果の検証

加来田博貴, 鄭暁霞, 小田博之, 原田隼, 大澤史宜, 藤井周司, 永澤秀子, アリ・ハメッド, 赤穂榮一, 佐々木健二, 杉本幸雄, 田井章博

日本薬学会年会要旨集 128年会 ( 2 ) 51 - 51 2008.3

RXRα/βデュアルアゴニストNEt-3IPの開発と生理活性評価

高松佳代, 高野敦史, 薬師寺信匡, 師橋一徳, 森下健一, 大澤史宜, 藤井周司, 松浦信康, 槇島誠, 永澤秀子, 杉本幸雄, 田井章博, 佐々木健二, 加来田博貴

日本薬学会年会要旨集 128年会 ( 2 ) 51 - 51 2008.3

RXRα/βデュアルアゴニストNEt-3IPの抗炎症及び抗がん作用の検証

高野敦史, 原田隼, ZHENG Xiaoxia, 薬師寺信匡, 森下健一, 大澤史宜, 藤井周司, 杉本幸雄, 田井章博, 槇島誠, 永澤秀子, 佐々木健二, 加来田博貴

メディシナルケミストリーシンポジウム講演要旨集 26th 2007

ベンゼンスルホンアニリドを骨格とする新規シクロオキシゲナーゼ阻害剤の開発

鄭暁霞, 小田博之, 片山健太郎, 赤穂栄一, Hamed I. Ali, 加来田博貴, 佐々木健二

日本薬学会年会要旨集 126年会 ( 4 ) 175 - 175 2006.3

ピューロマイシン感受性アミノペプチダーゼ(PSA)特異的阻害剤の構造活性相関

加来田博貴, 柏延之, 小磯邦子, 長澤和夫, 橋本祐一

日本薬学会年会要旨集 122年会 ( 3 ) 10 - 10 2002.3

ホモフタルイミド型特異的アミノペプチダーゼ阻害剤の構造活性相関

加来田博貴, 門矢静夫, 高橋裕保, 森崎尚子, 佐崎敬三, 橋本祐一

日本薬学会年会要旨集 121年会 ( 3 ) 21 - 21 2001.3

Enzyme Inhibitors Derived from Thalidomide

Hiroki Kakuta, Hiroyasu Takahashi, Sonei Sou, Tetsuya Kita, Kazuo Nagasawa, Yuichi Hashimoto

Recent Res. Devel. Med. Chem. 1, 189-211 2001

Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton

H Takahashi, M Komoda, H Kakuta, Y Hashimoto

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 120 ( 10 ) 909 - 921 2000.10

Language：Japanese Publishing type：Book review, literature introduction, etc. Publisher：PHARMACEUTICAL SOC JAPAN

The studies on both structure-activity relationship study and identification of the target enzyme of novel nonpeptide aminopeptidase inhibitors with cyclic imide skeleton are reviewed. Some N-phenylphthalimide or N-phenylhomophthalimide derivative showed potent protease inhibitory activity in an assay system using human acute lymphoblastic leukemia cells, Molt-4, with alanin-4-methylcoumaryl-7-amide (ala-AMC) as a substrate. Especially, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1, 3-dione (PIQ-22) (3) was found to be the most potent inhibitor and further it showed potent tumor-cell invasion inhibitory activity that is more effective than potent peptide aminopeptidase inhibitors such as bestatin (1) or actinonin (2). For the further investigation of this novel protease inhibitory activity, we have carried out the structural development of PIQ-22 (3) and it is assumed that tautomerism of imidobenzoylketone in cyclic imide structure may be related to the inhibitory activity. The requirement for the activity of electron donating groups such as NH2 or OH to the condensed phenyl ring in phthalimide inhibitors also supports this possibility. The target aminopeptidase of PIQ-22 was identified as puromycin-sensitive aminopeptidase (PSA), by N-terminal amino acid sequencing, and by comparison with chromatographic behavior and substrate-selectivity, and so on. Lineweaver-Burk plot showed that PSA is inhibited by PIQ-22 (3) in a noncompetitive manner while puromycin (83) and bestatin (1) inhibit PSA competitively.

DOI： 10.1248/yakushi1947.120.10_909

CiNii Article

Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton

H Takahashi, M Komoda, H Kakuta, Y Hashimoto

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 120 ( 10 ) 909 - 921 2000.10

Language：Japanese Publishing type：Book review, literature introduction, etc. Publisher：PHARMACEUTICAL SOC JAPAN

DOI： 10.1248/yakushi1947.120.10_909