JP2012510512A - 記憶を推進するためのhdac2の阻害 - Google Patents
記憶を推進するためのhdac2の阻害 Download PDFInfo
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- JP2012510512A JP2012510512A JP2011539506A JP2011539506A JP2012510512A JP 2012510512 A JP2012510512 A JP 2012510512A JP 2011539506 A JP2011539506 A JP 2011539506A JP 2011539506 A JP2011539506 A JP 2011539506A JP 2012510512 A JP2012510512 A JP 2012510512A
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- hdac2
- inhibitor
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- hdac1
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- WTWHYHPOGZUENL-KZKGWZQBSA-N trichostatin B Chemical compound O=C([C@H](C)/C=C(\C)/C=C/C(=O)NO[Fe](ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C=1C=CC(=CC=1)N(C)C)ONC(=O)\C=C\C(\C)=C\[C@@H](C)C(=O)C=1C=CC(=CC=1)N(C)C)C1=CC=C(N(C)C)C=C1 WTWHYHPOGZUENL-KZKGWZQBSA-N 0.000 description 1
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Abstract
Description
本発明は、NIHNS051874の下で、政府の援助で為された発明である。したがって、政府は本発明においてある権利を有する。
関連出願
本出願は、35USC§119の下に、2008年12月3日に出願された米国仮出願第61/119,698に対して優先権を主張し、その全内容は参照により本明細書に組み込まれる。
脳萎縮は、通常の加齢を通して起こり、損傷した学習および記憶に関連する神経変性疾患の早期の特徴である。前脳における広範な神経変性疾患を有するマウスモデルが報告されたのはつい最近である(1〜3)。これらのモデルのうちの1つは、バイトランスジェニックCK−p25Tgマウスであり、これは、様々な神経変性疾患に関与するタンパク質である(4)p25の発現がCamKIIプロモーターの制御下にあり、ドキシサイクリン食(doxycycline diet)でオンまたはオフに切り替えることができる(3、5)。6週間のp25発現の出産後誘導は、深刻なシナプスおよび神経脱落に付随する学習の損傷の原因となった。しかしながら、臨床前研究は未だ、実質的な神経脱落が起こった後の記憶喪失を回復するための戦略を十分探索していない。
中枢神経系の神経変性疾患は、しばしば損傷した学習および記憶と関連し、最終的には認知症へと導かれる。臨床前研究において大々的には取り組まれてこなかった重要な側面は、長期記憶の喪失およびこれらの記憶へのアクセスを再構築する戦略の探索である。いくつかの態様において、本発明は、シナプスおよび神経脱落がすでに起こった後での長期記憶へのアクセスを回復する方法を提供する。環境強化(EE)は、すでに顕著な脳萎縮および神経脱落が起こった後に、学習反応を復帰させ、長期記憶へのアクセスを再構築することが示された。また本明細書において、EEとエピジェネティックな変化との間の相関関係も示された。EEは、ヒストン尾部のアセチル化を増大させ、メチル化のレベルを変化させる。アセチル化の増加およびメチル化のレベルの変化が、海馬および大脳皮質のヒストン3(H3)およびヒストン4(H4)で観察された。次に、上昇したヒストンH3およびH4のアセチル化が、神経ネットワークの再配線を始動させる。
HDAC2阻害剤は、経口、静脈内、皮膚、皮下、鼻内、筋肉内、腹腔内、頭蓋内、または脳室内投与されてよい。
本方法はまた、HDAC2阻害剤の投与の後に、対象の認識機能を評価するステップを含んでもよい。さらに本方法は、脳血流または脳血液関門機能を評価することにより処置をモニターすることを伴ってもよい。
いくつかの態様において、HDAC2阻害剤は、選択的HDAC1/HDAC2阻害剤である。他の態様において、HDAC2阻害剤は、選択的HDAC1/HDAC2/HDAC3阻害剤である。ある態様において、HDAC2阻害剤は、選択的HDAC1/HDAC2/HDAC10阻害剤である。ある態様において、選択的HDAC1/HDAC2/HDAC10阻害剤は、BRD−6929である。他の態様において、HDAC2阻害剤は、選択的HDAC1/HDAC2/HDAC3/HDAC10阻害剤である。
の化合物である
他の態様において、式IVは
他の態様において、式IVは
の化合物である。
他の態様において、式VIは
の化合物である。
R3は、アリールまたはヘテロアリールである、
の化合物である。
他の態様において、式IIは
他の態様において、式IIは
の化合物である。
いくつかの態様において、式IIIは
の化合物である。
他の態様において、式Vは
脳組織への送達のための処方における、HDAC2阻害剤および薬学的に許容可能な担体の医薬組成物もまた提供される。いくつかの態様において、HDAC2阻害剤は、血液脳関門を横断するように処方される。
他の側面において、本発明は、HDAC2阻害剤の組成物であって、該HDAC2阻害剤が式I、IIおよびIIIの化合物からなる群から選択される、前記組成物である。
ヒストンデアセチラーゼの阻害剤(HDACis)により誘導された、増大したヒストン尾部アセチル化は、野生型のマウスにおいてだけでなく、神経変性のマウスモデルにおいても同様に、学習および記憶を促進する。HDACisの治療能力を役立てるには、認識増強とつながりがある特定のHDACファミリーメンバーの知識が求められる。HDAC1ではなくHDAC2のニューロン特異的な過剰発現が、樹状突起棘密度、シナプス数、シナプス可塑性および記憶形成を減少させたことが、本発明の側面にしたがって示されている。反対に、マウスにおける慢性的なHDAC阻害剤処置と同様、HDAC2の欠損がシナプス数および記憶促進の増大の結果となった。とりわけ、HDAC2過剰発現マウスの減少したシナプス数および学習損傷が、慢性HDACi処置によって完全によくなった。それに応じて、HDACi処置は、HDACi欠損マウスにおける記憶形成のさらなる促進はしなかった。さらに、プロモーター占有分析は、シナプス可塑性および記憶形成に関与する遺伝子のプロモーターとHDAC2が関連することを明らかにした。我々の結果は、HDAC2が、長期持続的なシナプスの変化の調節、次に学習および記憶のネガティブな制御において役割を果たすことを示している。
R3は、アリールまたはヘテロアリールである。いくつかの態様において、R1はHであり;R1およびR2はHであり;R1はメチル、エチル、プロピルまたはブチルであり;R3はアリールであり;R3はへテロアリールであり;R3はチエニルである。
本明細書で用いられる場合、「ハロゲン」という語は−F、−Cl、−Brまたは−Iを指定し;「スルフヒドリル」という語は−SHを意味し;およひ「ヒドロキシル」という語は−OHを意味する。
吸入による投与について、本発明の使用のための化合物は、例えば、ジクロロジフルオロメタン、トリクロロフルオロメタン、ジクロロテトラフルオロエタン、二酸化炭素または他の適切なガスなどの好適な噴射剤を使用して、加圧パックまたは噴霧器からエアロゾルスプレーのプレゼンテーションの形態で都合よく送達されてよい。加圧エアロゾルの場合、投与単位は、計量された量を送達するためのバルブを提供することによって決定してよい。吸入器または注入器で使用するためのカプセルと例えばゼラチンのカートリッジは、化合物とラクトースまたはデンプンなどの好適な粉末基剤の粉末混合物を含有して製剤化してよい。
化合物はまた、坐剤または停留浣腸、例えば、カカオバターまたは他のグリセリドなどの従来の坐剤基剤を含むもの、などの直腸または膣用組成物に処方することができる。
前述の製剤に加えて、化合物はまた、デポー製剤として製剤化することもできる。かかる長時間作用型の製剤は、好適なポリマーまたは疎水性材料(例えば、許容可能な油中のエマルジョンとして)またはイオン交換樹脂として、または難溶性誘導体として、例えば難溶性塩として、処方してよい。
別の好ましい態様において、本発明の組成物は、これに限定するものではないが、レシチン、タウロコール酸、およびコレステロールを含む生体適合性デタージェントと共に、またはこれに限定するものではないが、ガンマグロブリンと血清アルブミンを含む他のタンパク質と共に容器中に保存される。より好ましくは、本発明の組成物は、ヒトへの使用についてヒト血清アルブミンと共に貯蔵され、獣医学用途についてウシ血清アルブミンと共に貯蔵される。
方法
環境強化:4匹までのマウスを連続的に、自発的なランニングのための2つの車輪と、トンネルを作製するための様々なおもちゃ(Petcoから入手)およびよじ登りデバイスを含むケージに収容した。食料と水は自由摂取であった。食べ物は、睡眠中は隠していた。おもちゃと実行中の車輪は毎日変更した。
ターゲティングベクターpTH1とpTH2をSacIで直鎖状にし、V6.5(129XC57BL/ 6)F1胚性幹(ES)細胞株にエレクトロポレーションした。我々は96のネオマイシン耐性クローンを選び、そのうち46をサザンブロットで分析した。我々は、BamHI部位(左)およびEcoRI(右)で消化後、3’外部プローブのみを使用した。野生型クローンは8.8〜kbのバンドを呈示した。標的対立遺伝子は、正しいターゲットイベントで13kbまでのバンドシフトの結果となり、5個のクローンが正しく標的としていた。2つのクローンを使用して、(DBA/2XC57BL/6)F1の胚盤胞に注入してキメラを生成した。キメラは、雌のC57BL/6と交配し、子孫が生殖系伝達について分析した。ヘテロ接合性ノックイン株を混合バックグラウンドで維持し、それらを交配してホモ接合性動物を得た。3〜6カ月齢マウスを行動テストとさらなる分析のために使用した。
短時間記憶テストでは、記憶テストは、フットショックの訓練後3時間で実施された。
音刺激依存的恐怖条件付け。訓練は、訓練は、条件付けボックス(文脈)にマウスを3分曝露し、続いて音刺激[30秒、20kHz、75dBの音圧レベル(SPL)]およびフットショック(2秒、0.8mAの定電流)で構成された。記憶テストは、新たな文脈に続いて、さらに音刺激(10kHz、75dBのSPL)への3分の曝露することにより、24時間後に行われた。すくみは、上記のように、2人の偏りのない観察者によって10秒ごとに記録された。
各試験は、サンプル試行と選択試行で構成された。サンプル試行において、マウス擬似ランダムシーケンス(セッションあたりの左と右の順番が等しい数となり、2回を越えて連続して同じ方向はない)にしたがって、プラスチックのブロックの存在によって左右どちらかを余儀なくされた。0.07ミリリットルの甘いコンデンスミルク(水で50分の50に希釈)からなる報酬は、アームの端の食餌ウェル利用可能であった。ブロックを除去し、マウスをスタートアームの端に、実験者に向かって置き、どちらかのアームの自由な選択を許された。サンプル試行と選択試行の間の時間間隔は約15秒であった。動物は、前回未訪問であったアーム(すなわち二者択一のため)を選択する方に報酬が与えられた。マウスは、約10分の試験間間隔(ITI)で一度に1つの試験を試行した。それぞれの毎日のセッションは、4試験で構成され、そしてマウスは、合計で24の試験を受けた。
細胞をPBS中4%PFA/4%スクロースで固定した。固定液をPBSで洗い流し(3回の洗浄サイクル)、EGR1−GFPイメージングのために処理した。細胞(ウェルあたり3000〜5000)は、Cellomics ArrayScanの画像システムを用いて5倍の対物レンズでイメージングおよび分析をした。内蔵のTargetActivationアルゴリズムは、ヘキスト色素を使用して細胞をマークし、セル当たりの平均EGR1−GFP(ウェルあたり細胞あたりの平均蛍光強度)を計測するのに最適化された。データはコントロール(培地添加)に対して正規化した。
PCRに用いたプライマー配列:
例1:SAHAは、文脈的恐怖条件付けの訓練と記憶テストの前10日間、25mg/kgで腹腔内(ip)注射によって毎日投与した。驚くべきことに、生理食塩水処置群ではなくSAHA処置群が、顕著にHDAC2OEマウスのすくみ行動を増加させた(66.7±5.1%、n=12;26.9±5.9、n=12、p<0.0001、SAHA群対生理食塩水群、図1A)。同じトレーニングのパラダイムで、SAHA処置がWTコントロールマウスのすくみ行動を44.8±4.7%(n=15、生理食塩水コントロール)から63.9±4.2%(n=12、SAHA処置)に増加させたことに留意すべきである。したがって、SAHA処置後のHDAC2OEマウスのすくみレベルは生理食塩水処置HDAC2OEマウスが低いすくみ行動を示すという事実にもかかわらず、SAHAで処理したコントロールマウスのものと同等であった。それらと合致して、SAHA治療はHDAC2OEマウスにおける低減した樹状棘突起とシナプスの表現型を完全に廃止する(図1B、C)。
複数のHDAC阻害剤の酵素阻害活性を、既知のHDACのアイソフォームのいくつかに対して測定し、結果を図8に示す。SAHAを、参照混合クラスI−クラスII阻害剤として含む。BRD−6929は、このクラスの化合物は、HDAC8またはクラスIIのHDAC酵素を阻害しないことを示す。BRD番号の化合物のすべては、化合物のオルト−アニリドクラスから派生している。このクラスからの化合物すべてが、クラスIIのHDACと結合することが期待されているわけではない。
標準的なウェスタンブロッティング法を、HeLa細胞溶解物中のヒストンのアセチル化のマークにHDAC阻害剤の効果を測定するために用いた。一連の化合物は10μMで、6時間の間全HEK293細胞とともにインキュベートされた。ウェスタンブロットは、抗アセチルH4K12抗体と西洋ワサビペルオキシダーゼ標識二次抗体をルミノールベース基質(図9)と一緒に用いて、DMSOコントロールに対して増大したアセチル化レベルを示した。これは、これらのアナログの細胞性HDAC活性および特定のマーク、H4K12でのアセチル化における増大を実証する。生のウェスタンデータ(図10)の定量は、DMSOコントロールと比較して、複数選択的プロファイルはH4K12アセチル化のレベル向上に効果的であり、そのHDAC1,2とHDAC1,2,3選択的阻害剤が全細胞において特定のヒストン遺伝子座(H4K12)上に強いHDAC活性を有することを証明した。
標準的なウェスタンブロッティング法を、HeLa細胞溶解物中のヒストンのアセチル化のマークにおけるHDAC阻害剤の効果を測定するために使用した。HeLa細胞におけるウェスタンブロットの定量かおよびH4K12アセチル化のレベルに対する化合物処置の効果が図11に示されている。DMSOコントロールと比較して、アセチル化の様々な程度が観察された。HDAC1,2、HDAC1,2,3選択的化合物はH4K12遺伝子座でのアセチル化を増加させるのに有効であることがわかった。
図12は、HDAC阻害剤で処理したマウスの脳から分離された初代線条体細胞のウエスタンブロットを示している。3つの独立したサンプル/セットの2つのデータセットが提示されている。ウェスタンの定量化を表すヒストグラムもまた示されている。DMSOコントロールと比較して、BRD−6929は、ヒストン遺伝子座H4K12のアセチル化のレベルに顕著な影響を与える。BRD−6929処置は、1および10μMにおいて5〜10倍の増大の結果となる。BRD−6929は、HDAC1,2選択的な化合物であり、HDAC1,2対HDAC3において200倍の選択性を有している。これはHDAC1,2選択的化合物が効果的にHDAC2を阻害し、記憶、H4K12に関連付けられているアセチル化のマークを増加させることができることを示している。この場合、データはコントロールと比較した:SAHAとBRD−3696(CI−994)。HDAC1,2選択的化合物は、HDAC1,2,3阻害剤と汎阻害剤(すなわちSAHA)と同様にアセチル化を増加させる時に有効である。HDAC1、2の阻害は、このヒストン遺伝子座での増加したアセチル化に影響するのに十分である。
材料と方法:
1日目:
1)化合物を384ウェルプレート(Abgene)から185nlピンツールを用いて、ノータッチボトムプロトコルを用いて、ピン転送した。
2日目:後〜24時間の化合物処置−
1)培地は、プレートウォッシャー(Tecan)プロトコルを使用して、〜5μlの残量を残し、プレートの底に触れることなく)吸引し、または代替的に、12チャンネルアスピレーターワンドで、ウェルを穏やかに吸飲して培地を除去した。
2)マルチチャンネルピペットやの液体操作システム(例えばCombi、標準のチューブ、低速)を、75μlのホルムアルデヒド(PBS中4%)を追加するために使用し、ウェルは室温で10分間インキュベートした。
4)PBSを吸引し、100μlのブロッキング/透過化バッファ(PBS中0.1%のTriton−X100、2%BSA)を加え、室温でウェルを1時間インキュベートした。
5)ブロッキングバッファを吸引し、ブロッキング緩衝液で1:500に希釈した50μlの一次抗体を添加し、そしてウェルを4℃で一晩インキュベートした。
3日目:
1)一次抗体を吸引し、ウェルを100μlのブロッキング緩衝液で3回洗浄した
2)二次抗体50μlを、1:500に希釈し、Hoeschst(1:1000から10mg/mLの(16mM)ストック)を加え、ウェルの光退色を防止するために箔で覆い、室温で1.5時間インキュベートした。
3)ウェルを100μlのPBSで3回リンスし、そしてPBS100μlを追加し、プレートを密封した
4)その後、プレートをAcumen/IX Microで読取った
5)プレートを4℃で保存した。
1および10μMのBRD−6929は、脳の領域特異的初代培養(大脳皮質および線条体)の6時間のインキュベーションの後、全体の細胞数の増加または減少の原因とならなかった。10μMのでBRD−6929は、脳の領域特異的初代培養で6時間のインキュベーション(線条体)(図14)後のH4K12アセチル化の増加を引き起こす。1および10μMのBRD−6929とBRD−5298(HDAC1、2選択的阻害剤)は、初代神経細胞培養(図15、図16)で6時間のインキュベーション後に、H2Bアセチル化の顕著な増加を引き起こす。これは、HDAC1,2選択的化合物が特定のヒストン遺伝子座H2Bでのアセチル化を増加させるのに有効であることを示している。このヒストン遺伝子座のアセチル化の増加は、HDAC2の阻害または調節および学習および記憶に関連付けられている。我々の知る限り、特定の細胞型において、これらの特異的マークを引き起こすHDAC阻害的選択性を有する化合物の報告はない。
図17は、45mg/kgの単回投与BRD−6929を、腹膜内注射を介して全身的に投与した後の薬物動力学的データの概要を表す。5分〜24時間における、C−57マウスの血漿および脳におけるBRD−6929についての濃度−時間曲線が示されている。このデータは、BRD−6929は血液脳関門を横断し、脳全体で、HDAC1および2のIC50を超える濃度を達成することを実証する。脳Cmax(0.83μM)およびAUC(3.9μM)レベルは、酵素阻害に必要なin vitroの濃度でも上記の効果がある。
BRD−6929での急性処置や成体のオスのC57BL/6Jマウスの脳の特定の領域におけるヒストンアセチル化の対応する効果のための実験プロトコルを図18に示す。特定の脳切片のウェスタンブロット分析のための粗タンパク質溶解プロトコル。
1.解剖のために、脳組織を凍結させる:
A.氷上で凍結組織を解凍し、250μlの氷冷した懸濁バッファ中で直ちに注意深くホモジナイズする。
(100μlは、約2〜3立方ミリメートルの組織のために使用され;必要に応じて調整)
1.5mlの使い捨て乳棒(Fisher cat#03-392-100)
B.できるだけ早く、等量の2×SDSゲルローディングバッファを添加し、上下にピペッティングして混合する。
3.スムーズに23から25ゲージの皮下注射針(2〜3倍)を介して、または簡単に超音波処理(Alは、針の方法を使用して、問題なく動作した)して、粘性の染色体DNAをせん断する。気泡/発泡を避ける。
4.新しいチューブに上清を移す、室温で10分間10,000gでサンプルを遠心する。
5.タンパク質濃度に基づいて、必要に応じて分注しサンプル。
0.1MのNaCl、0.01MのTrisCl(pH7.6)、0.001MのEDTA(pH8.0)(ここまでのバッファは、室温で先に調製、貯蔵することができる)使用直前に、追加:1×ホスファターゼ/プロテアーゼ阻害剤カクテル(例:ThermoFisher"HALT"cat#78440)
5mMの酪酸ナトリウム(HDAC阻害剤)。
2×SDSゲルローディング緩衝液:
100mMのTrisCl(pH6.8)、4%SDS、20%グリセロール(ここまでのバッファーは室温で先に調製、貯蔵することができる)使用直前に、追加:200mmのジチオスレイトール(1Mストックから)5mMの酪酸ナトリウム(HDAC阻害剤)。
ウェスタンのゲル分析は、BRD−6929の毎日10日間の慢性投与後であっても、BRD−6929はマウスの脳におけるアセチル化のレベルに対して効果を発揮できることを示した。ウェスタンブロットは、ビヒクルコントロールと比較してテトラアセチル化H2Bの増加を示した(図21)。これは、HDAC1,2選択的化合物が効果的に慢性投与後の脳内の特定のアセチル化のマークのアセチル化レベル(テトラアセチル化H2B)を増加させることができることを示している。
C57/BL6 WTマウスに10日間ビヒクルまたはBRD−6929を注射した。11日目に、マウスは文脈恐怖条件付けパラダイム(訓練は条件付けボックス(文脈、TSE)へのマウスの3分の曝露および続くフットショック(2秒、0.8mAの定電流)からなる)。訓練の1時間後、マウスにBRD−6929またはビヒクルを注入した。12日目に、マウスは訓練ボックスに返され、すくみ行動を監視および記録された。
(E)−3−(4−((2−アセトアミドメチルアミノ)メチル)フェニル)−N−(2−アミノ−5−(チオフェン−2−イル)フェニル)アクリルアミド(BRD−9460)の合成
以下の4つの化合物は、2−(4−メチルピペラジン−1−イル)エタンアミンを2−フェニルエタンアミンで置き換えることおよび適切な安息香酸を活用することによって調製することができる。
本発明の少なくとも1つの実施形態のいくつかの側面を上記のように説明したが、当業者にとって容易な様々な変更、修正、および改良が起こることを理解すべきである。かかる変更、修正、および改良はこの開示の一部であることが意図されており、発明の精神および範囲内であることが意図される。したがって、前述の説明および図面は例示にすぎない。
Claims (53)
- 対象における記憶を増強する方法であって、対象における記憶の増強に有効な量で、対象にHDAC2阻害剤を投与することを含む、前記方法。
- HDAC2阻害剤が、選択的HDAC2阻害剤である、請求項1に記載の方法。
- 記憶が、長期記憶である、請求項1または2に記載の方法。
- 対象が、長期記憶へのアクセスの低下を有する、請求項1または2に記載の方法。
- 長期記憶が、損傷している、請求項4に記載の方法。
- 長期記憶の損傷が、加齢によるものである、請求項5に記載の方法。
- 長期記憶の損傷が、傷害によるものである、請求項5に記載の方法。
- 対象におけるシナプスネットワークが再構築される、請求項1または2に記載の方法。
- HDAC2阻害剤が、HDAC1阻害剤ではない、請求項1に記載の方法。
- HDAC2阻害剤が、HDAC5、HDAC6、HDAC7またはHDAC10阻害剤ではない、請求項1に記載の方法。
- HDAC3阻害剤を投与することをさらに含む、請求項1または2に記載の方法。
- HDAC11阻害剤を投与することをさらに含む、請求項1または2に記載の方法。
- 選択的HDAC2阻害剤が、siRNA、shRNA、miRNA、dsRNAまたはリボザイムなどのHDAC2 RNAiあるいはそれらの変異体である、請求項2に記載の方法。
- 記憶が、取り戻される、請求項1または2に記載の方法。
- DNAメチル化阻害剤を投与することをさらに含む、請求項1または2に記載の方法。
- DNAメチル化阻害剤が、5−アザシチジン、5−アザ−2’デオキシシチジン、5,6−ジヒドロ−5−アザシチジン、5,6−ジヒドロ−5−アザ−2’デオキシシチジン、5−フルオロシチジン、5−フルオロ−2’デオキシシチジン、および5−アザ−2’デオキシシトシン、5,6−ジヒドロ−5−アザ−2’デオキシシトシン、および5−フルオロ−2’デオキシシトシンを含む短鎖オリゴヌクレオチド、およびプロカインアミド、ゼブラリン、および(−)−エピガロカテキン−3−ガレートからなる群から選択される、請求項15に記載の方法。
- HDAC2阻害剤が、経口、静脈内、皮膚、皮下、鼻内、筋肉内、腹腔内、頭蓋内、または脳室内投与される、請求項1または2に記載の方法。
- 対象が、AMCI(軽度認識障害)、アルツハイマー病、記憶喪失、アルツハイマー病に関連する注意欠陥症状、アルツハイマー病に関連する神経変性、混合血管起源の認知症、変性起源の認知症、初老期認知症、老年性認知症、パーキンソン病に関連する認知症、血管性認知症、進行性核上性麻痺、または大脳皮質基底核変性症からなる群から選択される障害を有している、請求項1または2に記載の方法。
- HDAC2阻害剤の投与の後に、対象の認識機能を評価することをさらに含む、請求項1または2に記載の方法。
- 脳血流または脳血液関門機能を評価することにより処置をモニターすることをさらに含む、請求項18に記載の方法。
- 追加の治療剤を対象に投与することをさらに含む、請求項18に記載の方法。
- 追加の治療剤が、ARICEPTまたはドネペジル、COGNEXまたはタクリン、EXELONまたはリバスチグミン、REMINYLまたはガランタミン、抗アミロイドワクチン、Aベータ低下治療、頭の体操、または精神的刺激である、請求項21に記載の方法。
- アルツハイマー病を処置するための方法であって、アルツハイマー病を有する対象に、アルツハイマー病の処置に有効な量でHDAC2阻害剤を投与することを含む、前記方法。
- HDAC2阻害剤が、選択的HDAC2阻害剤である、請求項23に記載の方法。
- HDAC2阻害剤が、選択的HDAC1/HDAC2阻害剤である、請求項1または24に記載の方法。
- HDAC2阻害剤が、式(IV)
R3は、任意に置換されたアリール、任意に置換されたヘテロアリール、またはアリール−C1〜6アルキレンである、
の化合物である、請求項25に記載の方法。 - 式IVが、
- 式IVが、
- 式IVが、
- 式IVが、
- HDAC2阻害剤が、選択的HDAC1/HDAC2/HDAC3阻害剤である、請求項1または24に記載の方法。
- HDAC2阻害剤が、式(VI)
の化合物である、請求項31に記載の方法。 - 式VIが、
- HDAC2阻害剤が、式(I)
R3は、アリールまたはヘテロアリールである、
の化合物である、請求項1または24に記載の方法。 - 式Iが、
- HDAC2阻害剤が、式(II)
R3は、アリールまたはヘテロアリールである、
の化合物である、請求項1または24に記載の方法。 - 式IIが、
- 式IIが、
- 式IIが、
- 式IIが、
- 式IIが、
- HDAC2阻害剤が、式(III)
R1およびR2は、H、置換または非置換、分岐のまたは非分岐の、環式のまたは非環式のC1〜6アルキルから独立して選択され;および
R3は、アルキニル、アリールまたはヘテロアリールである、
の化合物である、請求項1または24に記載の方法。 - 式IIIが、
- 式IIIが、
- 式IIIが、
- HDAC2阻害剤が、式(V)
R3は、アリールまたはヘテロアリールである、
の化合物である、請求項1または24に記載の方法。 - 式Vが、
- HDAC2阻害剤および薬学的に許容可能な担体を含み、脳組織への送達のための処方である、医薬組成物。
- HDAC2阻害剤が血液脳関門を横断するように処方されている、請求項48に記載の組成物。
- 対象における記憶を増強するために用いる組成物であって、対象における記憶を増強するのに有効な量のHDAC2阻害剤を含む、前記組成物。
- 対象における記憶を増強するために有効な量での、HDAC2阻害剤の使用。
- HDAC2阻害剤が、選択的HDAC1/HDAC2/HDAC10阻害剤である、請求項1または24に記載の方法。
- HDAC2阻害剤が、選択的HDAC1/HDAC2/HDAC3/HDAC10阻害剤である、請求項1または24に記載の方法。
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