JP2009538898A - 糖尿病の進行を遅らせるためのgpcrアゴニストの使用 - Google Patents
糖尿病の進行を遅らせるためのgpcrアゴニストの使用 Download PDFInfo
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Abstract
Description
1)酵母レセプターアッセイ
酵母細胞ベースのレセプターアッセイについては既に文献に記載されている(例えば、Miret J. J. et al, 2002, J. Biol. Chem., 277:6881-6887; Campbell R. M. et al, 1999, Bioorg. Med. Chem. Lett, 9:2413-2418; King K. et al, 1990, Science, 250:121-123);WO99/14344;WO00/12704;および米国特許第6,100,042号参照)。簡潔に言えば、酵母細胞を操作して内因性の酵母G−α(GPA1)を除去し、複数の技術を用いて構築されたGタンパク質キメラで置き換えた。さらに、内因性の酵母α細胞GPCR、Set3を除去し、選択した哺乳類GPCRの相同的発現を可能にした。酵母においては、真核細胞において保存されているフェロモンシグナル伝達経路のエレメント(例えば、マイトジェン活性化タンパクキナーゼ活性)は、Fus1の発現を指揮する。ガラクトシダーゼ(LacZ)をFus1プロモーター(Fus1p)の制御下に置くことによって、レセプターの活性化が酵素の読み出しにつながるような系を開発した。
組換えヒトGPR119を発現する安定な細胞系を確立し、この細胞系をサイクリックAMP(cAMP)の細胞内レベルに対する化合物の効果を調べるために用いた。単層細胞をリン酸緩衝生理食塩水で洗浄し、1%DMSOを加えた刺激バッファー中の種々の濃度の化合物で37℃にて30分間刺激した。次いで、細胞を溶解し、cAMP含量をPerkin Elmer AlphaScreenTM(Amplified Luminescent Proximity Homogeneous Assay)cAMPキットを用いて測定した。バッファーおよびアッセイ条件は、製造元のプロトコルに記載のとおりにした。
GPR119アゴニストを前糖尿病状態の6週齢のdb/dbマウスを用いて調べた。マウスを12時間の明暗周期(7時に点灯)で飼育した。毎日9時にビークル(25%ag.Gelucire 44/14、p.o.)またはGPR119アゴニスト(100mg/kg p.o.(25%ag.Gelucire 44/14中))を21日間投与した。0、7、および21日目にグルコース(Glc)投与(1.5g/kg p.o.)による経口グルコース耐性試験(OGTT)を行った。同日、OGTT(11時)後に化合物を投与した。OGTT中、血液サンプル(20μL)をGlc投与から25、50、80および120分後に採取した。Glcレベルの測定用に血液サンプル20μLを尾から採取し、使い捨てのマイクロピペット(Dade Diagnosis Inc., Puerto Rico)に入れ、サンプルを480μLの溶血剤に加えた。次いで、希釈した溶血血液のアリコート20μL(2本)を、96ウェルアッセイプレートの180μLのトリンダーグルコース試薬(Sigma酵素(Trinder)比色法)に加えた。混合後、サンプルを室温にて30分間静置し、Glc標準(Sigmaグルコース/尿素窒素混合標準セット)に対して読み取った。Glc投与から30分後にインスリン試験用に血液サンプルを採取した。22日目に食後血糖値(Fed blood glucose level)を測定した。血漿5μLを用い、インスリン濃度を使用説明書にしたがって96ウェルELISAキット(Crystal Chem. Inc. #INSKR020 96アッセイ)を用いて測定した。
Claims (8)
- 必要とする患者に有効量のGPR119アゴニストを投与することを含んでなる、β細胞変性の処置のための方法。
- GPR119アゴニストが、β細胞機能の悪化および/またはアポトーシスまたはネクローシスによるβ細胞の喪失を阻害または減少させることにより、β細胞変性を処置する、請求項1記載の方法。
- GPR119アゴニストがβ細胞の数またはサイズを増大させる、請求項1記載の方法。
- GPR119アゴニストが、膵細胞をランゲルハンス島の機能的に活性な細胞に増殖させることにより、および/または非感受性のまたは傷害を受けた膵細胞をランゲルハンス島の機能的に活性な細胞に転換させる、請求項3記載の方法。
- 必要とする患者に有効量のGPR119アゴニストを投与することを含んでなる、前糖尿病状態の2型糖尿病への進行を遅らせる方法。
- 必要とする患者に有効量のGPR119アゴニストを投与することを含んでなる、2型糖尿病の進行を遅らせる方法。
- 処置される患者がヒトである、請求項1〜6のいずれかに記載の方法。
- GPR119アゴニストが経口で作用する小分子である、請求項1〜7のいずれかに記載の方法。
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GBGB0610746.0A GB0610746D0 (en) | 2006-06-01 | 2006-06-01 | Method of treatment |
PCT/GB2007/050313 WO2007138362A1 (en) | 2006-06-01 | 2007-06-01 | Use of gpcr agonists to delay progression of diabetes |
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JP2009538898A true JP2009538898A (ja) | 2009-11-12 |
JP2009538898A5 JP2009538898A5 (ja) | 2012-12-27 |
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JP2009512684A Pending JP2009538898A (ja) | 2006-06-01 | 2007-06-01 | 糖尿病の進行を遅らせるためのgpcrアゴニストの使用 |
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US (1) | US20090258816A1 (ja) |
EP (1) | EP2029124A1 (ja) |
JP (1) | JP2009538898A (ja) |
GB (1) | GB0610746D0 (ja) |
WO (1) | WO2007138362A1 (ja) |
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CA2697551C (en) | 2007-09-20 | 2013-03-12 | Irm Llc | Piperidine derivatives as modulators of gpr119 activity |
EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
WO2010056907A2 (en) * | 2008-11-12 | 2010-05-20 | The Scripps Research Institute | Compounds that induce pancreatic beta-cell expansion |
JP5378825B2 (ja) * | 2009-02-17 | 2013-12-25 | 出光興産株式会社 | Gpr119アゴニスト |
GB0904284D0 (en) | 2009-03-12 | 2009-04-22 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
GB0904285D0 (en) | 2009-03-12 | 2009-04-22 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
GB0904287D0 (en) | 2009-03-12 | 2009-04-22 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
WO2010149685A1 (en) * | 2009-06-24 | 2010-12-29 | Boehringer Ingelheim International Gmbh | New compounds, pharmaceutical composition and methods relating thereto |
KR20120046188A (ko) * | 2009-06-24 | 2012-05-09 | 뉴로크린 바이오사이언시즈 인코퍼레이티드 | 신규 화합물, 약제학적 조성물 및 이에 관련된 방법 |
WO2011113947A1 (en) | 2010-03-18 | 2011-09-22 | Boehringer Ingelheim International Gmbh | Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions |
GB201006167D0 (en) | 2010-04-14 | 2010-05-26 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
GB201006166D0 (en) | 2010-04-14 | 2010-05-26 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
US20160083733A1 (en) * | 2013-05-23 | 2016-03-24 | University Of Bremen | Novel treatment of metabolic diseases |
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US20090325924A1 (en) * | 2005-06-30 | 2009-12-31 | Stuart Edward | GPCR Agonists |
US7638541B2 (en) * | 2006-12-28 | 2009-12-29 | Metabolex Inc. | 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine |
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US20090258816A1 (en) | 2009-10-15 |
WO2007138362A1 (en) | 2007-12-06 |
GB0610746D0 (en) | 2006-07-12 |
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