JP5566482B2 - PTEN阻害剤またはMaxi−Kチャンネルオープナー - Google Patents
PTEN阻害剤またはMaxi−Kチャンネルオープナー Download PDFInfo
- Publication number
- JP5566482B2 JP5566482B2 JP2013002314A JP2013002314A JP5566482B2 JP 5566482 B2 JP5566482 B2 JP 5566482B2 JP 2013002314 A JP2013002314 A JP 2013002314A JP 2013002314 A JP2013002314 A JP 2013002314A JP 5566482 B2 JP5566482 B2 JP 5566482B2
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- Prior art keywords
- maxi
- cilostazol
- channel
- salt
- pten
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Description
(1)抗痙攣剤
(2)局所脳浮腫および神経性運動障害、認知障害、外傷性脳傷害、パーキンソン病、てんかん、片頭痛、およびアルツハイマー病の治療用神経保護剤
(3)痛みを制御するための薬物
(4)切迫性尿失禁、腸管の過剰運動、子宮収縮、不安症、およびうつ病の治療剤。
本発明は、活性成分として式(I)のテトラゾリルアルコキシカルボスチリル化合物またはその塩を含む新規なPTEN阻害剤または新規なMaxi−Kチャンネルオープナーを提供する。本発明は更に、テトラゾリルアルコキシカルボスチリル化合物(I)またはその塩をかかる治療が必要な患者に投与することからなる、PTENを阻害する方法およびMaxi−Kチャンネルを開口する方法を提供し、更に、PTENの阻害のための、並びにMaxi−Kチャンネルの開口のための、テトラゾリルアルコキシカルボスチリル化合物(I)またはその塩の使用を提供する。
TNF−αの刺激により増加するPTENリン酸化レベルが、本発明の代表的な化合物:シロスタゾールによって抑制される効果を試験した。
更に、本発明の代表的な化合物:シロスタゾールおよびいくつかの市販品として入手可能なMaxi−Kチャンネルオープナーまたは遮断薬によるMaxi−Kチャンネルの開口の効果を試験した。
TNF−αよって刺激されるPTENリン酸化レベルの増大におけるシロスタゾールの抑制効果:
物質:
細胞培養:SK−N−SH(KCLB 30011,ヒト脳神経芽細胞腫)細胞は、2 mM L−グルタミンおよび1.0mM ピルビン酸ナトリウムを含み、熱で不活性化された10%ウシ胎児血清(FBS)で補充されたイーグルの基礎培地(MEM)中で培養した。細胞は5%CO2中37℃で集密に増殖し、20継代未満で実験に用いた。
TNF−α溶液の調製:TNF−α(アップステイト バイオテクノロジー社,ニューヨーク州レークプラシッド)をリン酸緩衝された生理食塩水に溶解し、10μg/ml ストック溶液とした。
ウェスタンブロット分析法:集密的に培養された細胞を、TNF−αでの刺激の3時間前に、シロスタゾールを加えたFBSを1%含むMEM培地に交換し、次いで1時間TNF−αに曝した。
該細胞を50 mM トリス−Cl(pH 8.0)、150 mM NaCl、0.02% アジ化ナトリウム、100μg/ml フェニルメチルスルホニルフルオリド、1μg/ml アプロチニンおよび1%トライトンX−100を含む溶解緩衝液に溶解した。12,000rpmでの遠心分離に続いて、全タンパク質の50μgを8または10%SDS−PAGEゲルに負荷して、ニトロセルロース膜(アメルシャム ファルマシア バイオテック、ニュージャージー州ピスカタウェイ)に移した。ブロックされた膜は次いで指示抗体と共にインキュベートし、免疫反応性のバンドは、スーパーシグナル ウェスト ドゥラ エクステンディド デュレーション サブストレート キット(Supersignal West Dura Extended Duration Substrate Kit)(ピアス社、イリノイ州ロックフォード)で勧められているような化学発光剤を用いて可視化された。該バンドのシグナルはGS−710校正された画像デンシトメーター(バイオ ラド ラボラトリィズ、カリフォルニア州ハーキュリーズ)を用いて定量した。結果は相対密度として表した。PTEN、リン酸化−PTEN(Ser380/Thr382/383)に対するポリクローナル抗体は、セル シグナリング テクノロジー(マサチューセッツ州ベヴァリー)から得た。
統計解析:結果は平均±SEMとして表す。グループ間の統計的な差はスチューデントのt検定で決定した。p<0.05は有意であると考えた。
ウェウタンブロットおよびデンシトメーターによる濃度測定解析は添付の図1に示す。
図1からわかるように、シロスタゾール(1、10および100μM)濃度に依存してTNF−α (50 ng/ml)で刺激される増大したPTENリン酸化レベルを抑制した。
上記の実験の結果から、シロスタゾールがPTENリン酸化を阻害する強い活性を示すことは明らかである。
物質:
細胞培養:SK−N−SH(KCLB 30011,ヒト脳神経芽細胞腫)細胞は、2 mM L−グルタミンおよび1.0mM ピルビン酸ナトリウムを含み、熱で不活性化された10%ウシ胎児血清で補充されたイーグルの基礎培地(MEM)中で培養した。細胞は5%CO2中37℃で集密に増殖し、20継代未満で実験に用いた。
(1)シロスタゾール(本発明の化合物、6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)−ブトキシ]−3,4−ジヒドロ−カルボスチリルの商品名)
(2)グリベンクラミド(「GBC」と略される。一般名:グリブリド,化学名:5−クロロ−N−[2−[4−[[[(シクロヘキシルアミノ)カルボニル]アミノ]スルホニル]フェニル]エチル]−2−メトキシベンズアミド,市販品として入手可能な抗糖尿病薬,ATP感受性K+チャンネルの遮断薬である。)
(3)イベリオトキシン(「Ibtx」と略される。Maxi−K+チャンネル遮断薬として知られている。)
細胞全体のK+電流の記録:実験は倒立顕微鏡(ニコン製 TE300モデル,日本、東京)のステージ上に据え付けられ、1 ml/分の流速で絶えず灌流された小さな槽(0.5 mL)の中で行った。パッチクランプ技術の細胞全体の立体配置を用いて、K+電流を室温で(20〜22℃)アキソパッチ(Axopatch)−200B パッチクランプ増幅器(アクソン機器社(Axon Instruments), カリフォルニア州フォスターシティ)で記録した。0.5〜5kHzでアンチエイリアスフィルター処理した後、1〜10 kHzで電流を採取した。データの取得および命令の電位は、pClamp 6.0.3ソフトウェア(アクソン機器社(Axon Instruments), カリフォルニア州フォスターシティ)で制御した。電圧クランプの品質を保証するために、電極抵抗を3MΩ以下に保った。接合部電位は標準槽溶液中の電極でゼロにした。ギガオームシール形成(Gigaohm seal formation)は吸引によって行われ、細胞全体の立体構造を確立した後、-80mVから対称的10mV電位固定過程によって導かれた容量性過電流を、細胞電気容量の計算のため50kHzで記録した。細胞全体の記録用の通常の槽溶液は、130 mM NaCl、5 mM KCl、1.2 mM MgCl2、1.8 mM CaCl2、10 mM HEPES、5.2 mM ブドウ糖であり、pHはNaOHで7.4に調整された。ピペットは140 mM KCl、0.5 mM MgCl2、0.1 mM CaCl2、0.09 mM エチレンビス(オキソニトリロ)四酢酸(EGTA)、10 mM HEPES、10 mM ブドウ糖で満たし、pHはKOHで7.4に調整した。
細胞全体の記録を確立し、脱分極で導かれた電流が安定化するまで約5分間コントロール対照の記録を収集した後、シロスタゾールを該槽に適用した。グリベンクラミドまたはイベリオトキシンを用いる実験においては、シロスタゾールはグリベンクラミドまたはイベリオトキシンを投与した後約20分に該槽に適用した。
試験結果は添付の図2に示す。この中で図2Aはシロスタゾールの効果を示し、図2Bはシロスタゾールおよび/またはグリベンクラミド(「GBC」,Maxi−K+チャンネルの開口を示唆)の効果を示し、および図2Cはシロスタゾールおよび/またはイベリオトキシン(「Ibtx」,Maxi−K+チャンネル遮断薬)の効果を示す
図2からわかるように、電流はシロスタゾールによって有意に増加したが、一方、イベリオトキシン(100nM)の該槽への添加によって可逆的にブロックされたが、グリベンクラミド(10μM)ではブロックされなかった。Maxi−Kチャンネルで媒介される電流の増加は、グリベンクラミドの共存下でさえシロスタゾールによって得られ、一方、グリベンクラミド単独ではMaxi−Kチャンネルで媒介される電流は増加し得なかった。シロスタゾールがMaxi−Kチャンネル遮断薬であるイベリオトキシンと共に細胞に加えられた場合、電流の増加はイベリオトキシン単独よりやや少なかった。
1.化合物の調製
ベヒクル対照;0.5% カルボキシメチルセルロース、毎日2回(n=10)
シロスタゾール;100 mg/kg、毎日2回(n=10)
少量の粉末(シロスタゾール)をメノウ乳鉢ですりつぶす。0.5% カルボキシ−メチルセルロース(CMC)を2、3滴加え、よくすりつぶす。4〜5mlの0.5%CMCを加え、懸濁したシロスタゾールを遮光された瓶に戻す。
1000 mg/50mlの濃度で毎週の試験化合物を調製し、および4℃での遮光下保存する。
化合物の投与:
投与前、超音波ソニケーターで試験化合物のストック瓶を超音波処理し、よく混ぜる。
化合物は各群毎に毎日2回経口で強制投与。
ベヒクル対照(0.5% カルボキシメチルセルロース:CMC; 1kg/5ml)は毎日2回強制投与。試験化合物(シロスタゾール; 100 mg/kg/5ml)は毎日2回強制投与。
a.動物(8週齢,変異体ヒトAPPK670N,M6711/系 Tg2576を発現する半接合性遺伝子組み換えマウス)を、2群の二重の遺伝子組み換えAPP/PS1マウス(対照群およびシロスタゾール群,全数=20マウス)にランダムに分けた。以下の表に示すように、各マウスに6週間強制投与法で毎日2回投与した。
b.マウスは試験の開始時と終了時に遺伝子型を同定した。
c.マウスは生存期が完了する前までY字型迷路行動試験を受けさせた。
d.マウスは14週齢で屠殺した。
e.屠殺後、1 mLの血液をシロスタゾールの血中濃度測定用に集め、APP/PS1マウスを生理食塩水で灌流した。脳は二等分し、一方の半球は固定し、他方の半球は凍結した。
f.凍結した半球はホモジネートし、ELISAで全アミロイドベータ濃度を分析した。
マウスの脳における全A−ベータ40および全A−ベータ42レベルを、対照群とシロスタゾール処置群で測定した。結果は添付の図3に示す。
以下の方法は「Y字型迷路における自発的交替」の試験を行うのに取られる過程を概説する。マウスは周りを探し回る生来の性質を有する。探索が成功するかは、短時間前に訪れた場所(食物が枯渇または存在しない)を避ける能力に依存する(「自発的交替」)。Y字型迷路は報酬の引渡しを含まない行動学に基づく試験である。損なわれた「作業記憶」機能を有するマウスは、作業記憶内に、今まさに訪れた場所に関する情報を保持することができない。従って自発的交替の減少を示す。
開示した結果では、自発的交替の減少と、ある遺伝子組み換えマウスの系統、例えばAPP/PS1マウスにおける探索の増加を示している。
シロスタゾールは抗血小板および血管拡張活性を有し、ASOの適用を有し、二次的脳梗塞を予防する。
これらのシロスタゾールの活性は、アミロイドベータタンパク質の析出を減少させるのに寄与し得、アルツハイマー病の痴呆の行動を改善し得る。
1:赤
2:緑
3:青
4:黒
Y字型迷路行動パラダイムから得られた結果を添付の図4にまとめる。
Claims (6)
- 6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)ブトキシ]−3,4−ジヒドロカルボスチリルまたはその塩を活性成分として含むMaxi−Kチャンネルオープナー。
- 活性成分として6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)ブトキシ]−3,4−ジヒドロカルボスチリルまたはその塩、および通常の医薬的に許容される担体または希釈剤を含む、Maxi−Kチャンネルを開口するための医薬組成物。
- Maxi−Kチャンネルの開口用薬剤の製造のための、6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)ブトキシ]−3,4−ジヒドロカルボスチリルまたはその塩の使用。
- 6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)ブトキシ]−3,4−ジヒドロカルボスチリルまたはその塩を活性成分として含むTNF−αによって刺激されるPTENリン酸化の阻害剤。
- 活性成分として6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)ブトキシ]−3,4−ジヒドロカルボスチリルまたはその塩、および通常の医薬的に許容される担体または希釈剤を含む、TNF−αによって刺激されるPTENリン酸化を阻害するための医薬組成物。
- TNF−αによって刺激されるPTENリン酸化の阻害剤を製造するための、6−[4−(1−シクロヘキシル−1H−テトラゾール−5−イル)ブトキシ]−3,4−ジヒドロカルボスチリルまたはその塩の使用。
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