Faculty Profiles - KAKUTA Hiroki

MISC - KAKUTA Hiroki

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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

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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

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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

[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

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[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

Web of Science

PubMed

researchmap

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

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

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

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

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

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

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