JP4691041B2 - Gtpアーゼ阻害剤および使用方法 - Google Patents
Gtpアーゼ阻害剤および使用方法 Download PDFInfo
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- 0 Cc1nc(ccc(Nc2nc(NC(CCCN(*)*)O*)nc(C)c2)c2)c2c(N)c1 Chemical compound Cc1nc(ccc(Nc2nc(NC(CCCN(*)*)O*)nc(C)c2)c2)c2c(N)c1 0.000 description 1
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Description
[式中、R1〜R2は、H、-X-Alk、-X-Alk-X'、および-X-Y-X'からなる群より独立して選択され、ここで、Xは-CR7R8であり、X'は-CHR7R8であり、AlkはC2-C18置換または無置換炭化水素鎖であり、YはC2-C8置換または無置換アルキレン鎖であり、R6はHまたは(C1-C4)アルキルであり、そしてR7およびR8はHまたは(C1-C4)アルキルからなる群より独立して選択される]
または式(IIa)の化合物の塩を有する、安全有効量の少なくとも一つの化合物を投与することを含む方法を含む。
[式中、R10〜R12は、H、ハロ、(C1-C4)アルキル、分岐(C3-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、NO2、およびNH2からなる群より独立して選択される]
または式(III)の化合物の塩を有する。
[式中、R1〜R2は、H、-X-Alk、-X-Alk-X'、および-X-Y-X'からなる群より独立して選択され、ここで、Xは-CR7R8であり、X'は-CHR7R8であり、AlkはC2-C18置換または無置換炭化水素鎖であり、YはC2-C8置換または無置換アルキレン鎖であり、R6はHまたは(C1-C4)アルキルであり、そしてR7およびR8はHまたは(C1-C4)アルキルからなる群より独立して選択される]
または式(IIa)の化合物の塩を有する化合物の使用を含む。
組換えタンパク質生産.pET発現系(Novagen)を使用することにより、N末端DH/PHモジュールを含有する組換えTrio(残基1225-1537)、Rac1、Cdc42およびPAK1のp21結合ドメイン(PBD)(残基51-135)を、大腸菌BL21(DE3)株中で、N末端His6タグ付き融合タンパク質として発現させる。pGEX-KGベクターを使用することにより、Rac1、Cdc42、インターセクチン(Intersectin)、PAK1(PBD)およびWASP(PBD)を、大腸菌DH5α株中で、GST融合物として発現させる。N末端タグ付きGSTまたはHis6融合タンパク質は、グルタチオン-またはNi2+-アガロースアフィニティークロマトグラフィーによって精製する。グルタチオンビーズ上のGST-Rho GTPアーゼを、溶離させる。50mM Trio-HCl(pH7.6)、100mM NaCl、1mM EDTA、および1mM DTTを含有する緩衝剤で洗浄することにより、結合したグアニンヌクレオチドまたはMg2+から溶離させる。
Rac1特異的阻害剤の仮想スクリーニング.Rac1-Tiam1の三次元(3D)構造において、Rac1のTrp56は、Tiam1のHis1178、Ser1184、Glu1183、およびIle1197ならびにRac1のLys5、Val7、Thr58、およびSer71によって形成されるポケットに埋まっている(Worthylakeら,2000、これは参照によりその全文が本明細書に組み入れられる)。Trp56を取り巻く構造上の特徴に基づいてRac1特異的阻害剤を同定するために、潜在的阻害剤結合ポケットを、Rac1-Tiam1モノマー中でTrp56の6.5オングストローム以内にあるRac1の残基(Lys5、Val7、Trp56、およびSer71を含む)で作る。3Dデータベース検索を行なって、その結合ポケットにフィットするであろうコンフォメーションを持つ化合物を同定する。スクリーニング過程で化合物の可撓性を考慮するために、プログラムUNITY(そのDirected Tweakアルゴリズムは迅速かつコンフォメーション的にフレキシブルな3D検索を可能にする)(Hurst,1994、これは参照によりその全文が本明細書に組み入れられる)を適用する。
合成スキーム1
合成スキーム2
全般:
原材料はAldrich、Acros、FisherまたはMatrix Scientifyから購入した。溶媒は全てACS等級以上とした。反応は必要に応じて乾燥窒素雰囲気下で行なった。「減圧下」での溶媒除去とは、Buchi装置を使って25〜50℃および45Torrでのロータリーエバポレーションを指す。減圧乾燥は高減圧下で行なった。NMRスペクトルは全てVarian-Gemini 300分光光度計を使って、1H NMRについてはCHCl3(7.26ppm)またはDMSO(2.5ppm)を参照物質として300MHzで、また13C NMRの場合はCDCl3(77.0ppm)またはDMSO(39.43)を参照物質として75MHzで記録した。
1HNMR(DMSO)δ10.22(s,1H),9.97(s,1H),7.57(d,2H),7.11(d,2H),4.65(s,1H),3.56(s,3 H),2.04(s,3H),1.94(s,3H);13CNMR(DMSO)δ169.64,168.07,159.33,136.48,133.55,124.52,119.44,84.47,49.77,23.81,19.68.
1HNMR(DMSO)δ11.52(br,s,1H),10.07(s,1H),8.24(s,1H),7.82(d,1H),7.42(d,1H),5.84(s,1H),2.31(s,3H),2.05(s,1H)
1HNMR(DMSO)δ10.18(s,1H),8.46(s,1H),7.76(m,2H),6.84(s,1H),3.99(s,3H),2.55(s,3H),2.09(s,3H);13CNMR(DMSO)δ168.36,160.99,158.07,144.86,135.87,128.27,122.78,119.26,108.80,101.20,55.69,25.08,23.97
1HNMR(DMSO)δ7.41(m,1H),6.95(m,2H),6.30(s,1H),6.03(br,s,2H),5.05(br,s,2H),2.32(s,3H);13CNMR(DMSO)δ153.42,149.46,144.28,142.09,128.84,120.59,118.60,102.15,101.11,24.42
MS[M+1]=300p302;13CNMR(DMSO)δ167.51,162.58,159.22,157.61,151.05,145.99,133.17,128.96,125.39,117.38,114.23,102.45,102.26,24.68,23.19.
参考文献
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Claims (10)
- 請求項1または2記載の薬剤であって、前記適応症が、白血病、前立腺癌、卵巣癌、膵癌、肺癌、乳癌、肝癌、頭頸部癌、結腸癌、膀胱癌、非ホジキンリンパ腫癌および黒色腫からなる群より選択される、薬剤。
- 前記適応症が異常細胞増殖である、請求項1または2に記載の薬剤。
- 前記適応症が癌細胞増殖である、請求項1または2に記載の薬剤。
- 前記適応症が高血圧、アテローム性動脈硬化、再狭窄、脳虚血、脳血管痙攣、ニューロン変性、脊髄傷害、乳房癌、結腸癌、前立腺癌、卵巣癌、脳または肺の癌、血栓性障害、喘息、緑内障、骨粗鬆症および勃起機能障害からなる群より選択される、請求項1または2に記載の薬剤。
- N6-(2-((4-(ジエチルアミノ)-1-メチルブチル)アミノ)-6-メチル-4-ピリミジニル)-2-メチル-4,6-キノリンジアミンおよび医薬的に許容できる担体を含む医薬組成物。
- N6-(2-((4-(ジエチルアミノ)-1-メチルブチル)アミノ)-6-メチル-4-ピリミジニル)-2-メチル-4,6-キノリンジアミン化合物が少なくとも1重量%である、請求項8に記載の医薬組成物。
- さらに、ファルネシルタンパク質トランスフェラーゼ阻害剤、プレニル-タンパク質トランスフェラーゼ阻害剤、ゲラニルゲラニル-タンパク質トランスフェラーゼ阻害剤、およびそれらの組合せからなる群より選択される追加の医薬活性剤をさらに含む、請求項8に記載の医薬組成物。
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JP2003515604A (ja) * | 1999-11-29 | 2003-05-07 | アベンテイス・フアルマ・ソシエテ・アノニム | アリールアミン誘導体およびそれらの抗−テロメラーゼ剤としての使用 |
WO2002036586A1 (en) * | 2000-11-06 | 2002-05-10 | Astrazeneca Ab | N-type calcium channel antagonists for the treatment of pain |
JP2004513125A (ja) * | 2000-11-06 | 2004-04-30 | アストラゼネカ・アクチエボラーグ | 疼痛治療のためのn−型カルシウムチャンネル拮抗薬 |
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EP1691812A4 (en) | 2010-01-13 |
US20060004032A1 (en) | 2006-01-05 |
CA2546727A1 (en) | 2005-06-09 |
EP1691812A1 (en) | 2006-08-23 |
US7517890B2 (en) | 2009-04-14 |
CA2546727C (en) | 2012-10-02 |
JP2007512363A (ja) | 2007-05-17 |
WO2005051392A1 (en) | 2005-06-09 |
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