Drug discovery of utilizing of characteristics of angiotensin II type 1 receptor blockers

• Project/Area Number: 21591065
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Fukuoka University
• Principal Investigator: MIURA Shinichiro 福岡大学, 医学部, 准教授 (20343709)
• Co-Investigator(Kenkyū-buntansha): SAKU Keijiro 福岡大学, 医学部, 教授 (40183371)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ドラックエフェクト / クラスエフェクト / イノシトールリン酸産生能 / 細胞外シグナル調節キナーゼ活性 / 洗い流し試験 / 結合能 / インバースアゴニズム / monocyte chemoattractant protein / nuclear factor kappa B / peroxisome proliferator-activated receptor

Research Abstract

We analyzed the drug(molecular or differential) effects of angiotensin II type 1(AT1) receptor blockers. We found that candesartan has strong blocking effect of cell signaling after wash-out. In addition, irbesartan has a strong anti-inflammation and valsatan showed a highly selective behavior for AT1 receptor. Before designing a new ARB, we identified the olmesartan, olmesartan-related compound R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively.

Research Products

• [Journal Article] Abilities of candesartan and other AT_1 receptor blockers to impair angiotensin II-induced AT_1 receptor activation after washout (2012)
  • Author(s): Kiya Y, Miura S, Matsuo Y, Karnik SS, Saku K.
  • Journal Title: J Renin Angiotensin Aldosterone Syst Volume: (in press)
  • Peer Reviewed
• [Journal Article] Efficacy and Safety of Angiotensin II Type 1 Receptor Blocker/Calcium Channel Blocker Combination Therapy : Focus on a Single-pill Fixed-dose Combination of Valsartan/Amlodipine (2012)
  • Author(s): Miura S, Saku K.
  • Journal Title: J Int Med Res Volume: 40 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Abilities of candesartan and other AT_1 receptor blockers to impair angiotensin II-induced AT_1 receptor activation after washout (2012)
  • Author(s): Kiya Y, Miura S, Matsuo Y, Karnik SS, Saku K
  • Journal Title: J Renin Angiotensin Aldosterone Syst Volume: 13 Pages: 76-83
  • Peer Reviewed
• [Journal Article] Efficacy and safety of angiotensin II type 1 receptor blocker/calcium channel blocker combination therapy for hypertension : focus on a single-pill fixed-dose combination of valsartan and amlodipine (2012)
  • Author(s): Mura S, Saku K
  • Journal Title: J Int Med Res Volume: 40 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor blockers : Class effects vs. Molecular effects (2011)
  • Author(s): Miura S, Karnik SS, Saku K.
  • Journal Title: J Renin Angiotensin Aldosterone Syst Volume: 12 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor blockers : Class effects vs.Molecular effects (2011)
  • Author(s): Miura S, Karnik SS, Saku K
  • Journal Title: J Renin Angiotensin Aldosterone Syst Volume: 12 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of the antagonistic action between AT1 and AT2 receptors (2010)
  • Author(s): Miura S, Matsuo Y, Kiya Y, Karnik SS, Saku K.
  • Journal Title: Biochem Biophys Res Commun Volume: 391 Pages: 85-90
  • Peer Reviewed
• [Journal Article] A small difference in the molecular structure of AT_1 receptor blockers induces AT_1 receptor-dependent and independent beneficial effects (2010)
  • Author(s): Fujino M, Miura S, Kiya Y, Tominaga Y, Matsuo Y, Karnik SS, Saku K.
  • Journal Title: Hypertens Res Volume: 33 Pages: 1044-1052
  • Peer Reviewed
• [Journal Article] Clinical and pharmacotherapeutic relevance of the double chain domainof the angiotensin II type 1 receptor blocker olmesartan. (2010)
  • Author(s): Kiya Y, Miura S, Fujino M, Imaizumi S, Karnik SS, Saku K.
  • Journal Title: Clin Exp Hypertens. Volume: 32 Pages: 129-136
  • Peer Reviewed
• [Journal Article] Asmall difference in the molecular structure of AT_1 receptor blockers induces AT_1 receptor dependent and -independent beneficial effects. (2010)
  • Author(s): Fujino M, Miura S, Kiya Y, Tominaga Y, Matsuo Y, Karnik SS, Saku K.
  • Journal Title: Hypertens Res. Volume: 33 Pages: 1044-1052
  • Peer Reviewed
• [Journal Article] ARBのクラスエフェクトとドラッグエフェクト (2010)
  • Author(s): 木谷嘉博、三浦伸一郎
  • Journal Title: 血圧 Volume: 17 Pages: 698-703
• [Journal Article] Molecular mechanisms of the antagonistic action between ATI and AT2 receptors (2010)
  • Author(s): Miura S, Matsuo Y, Kiya Y, Karnik SS, Saku K.
  • Journal Title: Biochem Biophys Res Commun 391 Pages: 85-90
  • Peer Reviewed
• [Journal Article] Binding sites of valsartan, candesartan and losartan with angiotensin II receptor 1 subtype by molecular modeling (2009)
  • Author(s): Bhuiyan MA, Ishiguro M, Hossain M, Nakamura T, Ozaki M, Miura S, Nagatomo T.
  • Journal Title: Life Sci Volume: 85 Pages: 136-140
  • Peer Reviewed
• [Journal Article] Multivalent ligand-receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation (2009)
  • Author(s): Qin Y, Yasuda N, Akazawa H, Ito K, Kudo Y, Liao CH, Yamamoto R, Miura S, Saku K, Komuro I.
  • Journal Title: Hypertens Res Volume: 32 Pages: 875-883
  • Peer Reviewed
• [Journal Article] Constitutively active mutant N111G of angiotensin II type 1(AT1) receptor induced homologous internalization through mediation of AT1-receptor antagonist (2009)
  • Author(s): Bhuiyan MA, Hossain M, Miura S, Nakamura T, Ozaki M, Nagatomo T.
  • Journal Title: J Pharmacol Sci Volume: 111 Pages: 227-234
  • Peer Reviewed
• [Journal Article] Multivalent ligand-receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation (2009)
  • Author(s): Qin Y, Yasuda N, Akazawa H, Ito K, Kudo Y, Liao CH, Yamamoto R, Miura S, Saku K, Komuro I.
  • Journal Title: Hypertens Res 32 Pages: 875-883
  • Peer Reviewed
• [Journal Article] イルベサルタン―心腎連関をターゲットにした降圧療法 (2009)
  • Author(s): 三浦伸一郎
  • Journal Title: Prog Med 29 Pages: 111-119
• [Journal Article] ARBの特性と新たな創薬の可能性 (2009)
  • Author(s): 三浦伸一郎
  • Journal Title: Heart View 13 Pages: 86-92
• [Journal Article] アンジオテンシンII受容体のダイマー形成の病態生理学的意義 (2009)
  • Author(s): 木谷嘉博, 三浦伸一郎
  • Journal Title: 医学の歩み 228 Pages: 400-404
• [Journal Article] 「新規ARBに期待するもの」基礎:受容体結合と抗炎症作用 (2009)
  • Author(s): 三浦伸一郎
  • Journal Title: 血圧 16 Pages: 477-481
• [Journal Article] JSH2009から学ぶCKD合併患者の降圧治療―イルベサルタンの腎障害抑制メカニズム― (2009)
  • Author(s): 三浦伸一郎
  • Journal Title: Trapuetic Res 30 Pages: 493-499
• [Presentation] RAAS抑制薬による降圧療法 (2012)
  • Author(s): 三浦伸一郎
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-09
• [Presentation] ARBは成熟したのか?～イルベサルタンのペンタゴンアタッチメントを識る～ (2011)
  • Author(s): 三浦伸一郎
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 長崎
  • Year and Date: 2011-11-09
• [Presentation] ARBは成熟したのか?～イルベサルタンのペンタゴンアタッチメントを識る～ (2011)
  • Author(s): 三浦伸一郎
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
  • Year and Date: 2011-11-09
• [Presentation] ARBのClass effectsとDrug effects (2010)
  • Author(s): 三浦伸一郎
  • Organizer: 第47回日本臨床生理学会総会、ランチョンセミナー2
  • Place of Presentation: 前橋
  • Year and Date: 2010-11-19
• [Presentation] ARBのClass effectsとDrug effects (2010)
  • Author(s): 三浦伸一郎
  • Organizer: 第47回日本臨床生理学会総会
  • Place of Presentation: 前橋
  • Year and Date: 2010-11-19
• [Presentation] RBの化学構造の違いを臨床に活かせるか?～イルベサルタンのペンタゴンアタッチメントが生み出す特性～ (2010)
  • Author(s): 三浦伸一郎
  • Organizer: 第33回日本高血圧学会
  • Place of Presentation: 福岡
  • Year and Date: 2010-10-16
• [Presentation] ARBの化学構造の違いを臨床に活かせるか?～イルベサルタンのペンタゴンアタッチメントが生み出す特性～ (2010)
  • Author(s): 三浦伸一郎
  • Organizer: 第33回日本高血圧学会
  • Place of Presentation: 福岡
  • Year and Date: 2010-10-16
• [Presentation] ARBの化学構造の違いを臨床に活かせるか (2010)
  • Author(s): 三浦伸一郎
  • Organizer: 第75回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-08-03
• [Presentation] イルベサルタンのAT1受容体非依存性効果-ロサルタンとの比較 (2010)
  • Author(s): 木谷嘉博、三浦伸一郎、藤野正礼、Sadashiva S Karnik、朔啓二郎
  • Organizer: 第33回日本高血圧学会
  • Place of Presentation: 福岡
• [Presentation] A small difference in the molecular structure of AT1 receptor blockers induces AT1 receptor-dependent and-independent beneficial effects (2010)
  • Author(s): Kiya Y, Miura S, Fujino M, Karnik SS, Saku K.
  • Organizer: 第14回日本心血管内分泌代謝学会
  • Place of Presentation: Nara, Japan
• [Presentation] 高血圧患者の病態に合わせたARBの選択は可能か (2010)
  • Author(s): 三浦伸一郎
  • Organizer: The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto, Japan
• [Presentation] Differences between Angiotensin II-and Mechanical Stretch-induced Changes in the Conformation of Transmembrane III in an AT1 Receptor (2010)
  • Author(s): Kiya Y, Miura S, Fujino M, Akazawa H, Komuro I, Saku K.
  • Organizer: The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto, Japan
• [Presentation] Differences between Angiotensin II- and Mechanical Stretch-induced Changes in the Conformation of Transmembrane III in an AT1 Receptor (2010)
  • Author(s): Kiya Y, Miura S, Fujino M, Akazawa H, Komuro I, Saku K.
  • Organizer: The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto, Japan
• [Presentation] 高血圧患者の病態に合わせたARBの選択は可能か? (2010)
  • Author(s): 三浦伸一郎
  • Organizer: The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto, Japan.
• [Presentation] ARBのクラスエフェクトとドラッグエフェクト (2009)
  • Author(s): 三浦伸一郎
  • Organizer: 第32回日本高血圧学会
  • Place of Presentation: 大津
  • Year and Date: 2009-10-01
• [Presentation] オルメサルタンのダブルチェーンドメインの臨床・薬理的な有用性 (2009)
  • Author(s): 木谷嘉博、三浦伸一郎、藤野正礼、朔啓二郎
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Molecular mechanisms of AT2 receptor as a dominant negative receptor against AT1 receptor-induced cell signaling (2009)
  • Author(s): Miura S, Mastuo Y, Kiya Y, Saku K.
  • Organizer: The 26^<th> Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: Sapporo
• [Presentation] 降圧療法のココがポイント (2009)
  • Author(s): 三浦伸一郎
  • Organizer: 第47回日本社会保険医学会総会
  • Place of Presentation: 長崎
• [Presentation] Molecular mechanisms of AT2 receptor as a dominant negative receptora gainst AT1 receptor-induced cell signaling (2009)
  • Author(s): Miura S, Mastuo Y, Kiya Y, Saku K.
  • Organizer: The 26^<th> Annual Meeting of the International Societv for Heart Research Japanese Section
  • Place of Presentation: Sapporo