JP5852658B2 - デユビキチナーゼ阻害剤およびその使用方法 - Google Patents
デユビキチナーゼ阻害剤およびその使用方法 Download PDFInfo
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Description
本出願は、2010年9月24日に出願された米国特許仮出願第61/386,057号に基づく優先権を主張し、当仮出願に記載された全ての記載内容は参照により本明細書に組み込まれる。
R3は、アミノアルキレンアリールまたは置換アミノアルキレンアリールであり、
R4は、CN、アミノ、置換アミノ、アミド、置換アミド、アルキレンチオエーテル、置換アルキレンチオエーテル、アルキル、置換アルキル、アジド、アルキレンアジド、および置換アルキレンアジドからなる群から選択され、
R5は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アルコキシ、置換アルコキシ、アルキレンアリール、置換アルキレンアリール、チオエーテル、置換チオエーテル、アミノ、置換アミノ、ハライド、ヒドロキシ、ニトロ、およびSHからなる群から選択され、
R6は、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクロアルケニル、置換ヘテロシクロアルケニル、ヘテロシクロアルキル、置換ヘテロシクロアルキル、アルキレンアリール、置換アルキレンアリール、アルキレンヘテロアリール、置換アルキレンヘテロアリール、アルキレンヘテロシクロアルケニル、置換アルキレンヘテロシクロアルケニル、アルキレンヘテロシクロアルキル、および置換アルキレンヘテロシクロアルキルからなる群から選択される)の化合物またはその塩と接触させる。
脱ユビキチン化酵素(すなわち、デユビキチナーゼまたはDUB)は、一般にシステインプロテアーゼであり、サブグループとしてユビキチン特異的プロテアーゼ(USP)とユビキチンC末端加水分解酵素(UCH)に分類され得る。DUBの例としては、例えば、USP5、USP6、USP4、USP8、USP13、USP2、USP11、USP14、USP7、USP9X、USP10、USP1、USP12、USP16、USP15、USP17、USP19、USP20、USP3、USP9Y、USP18、USP21、USP22、USP33、USP29、USP25、USP36、USP32、USP26、USP24、USP42、USP46、USP37、USP28、USP47、USP38、USP44、USP50、USP35、USP30、Mername−AA088ペプチダーゼ、Mername−AA091ペプチダーゼ、USP45、USP51、USP34、USP48、USP40、USP31、Mername−AA129ペプチダーゼ、USP49、USP17様ペプチダーゼ、USP54、USP53、USP39、UCH−L1、UCH−L3、UCH−BAP1、UCH37、セザンヌ脱ユビキチン化ペプチダーゼ、セザンヌ2、腫瘍壊死因子α誘導タンパク質3、TRABIDタンパク質、VCP(p97)/p47相互作用タンパク質、オツバイン(otubain)1、オツバイン2、CylDタンパク質、SENP1ペプチダーゼ、SENP3ペプチダーゼ、SENP6ペプチダーゼ、SENP2ペプチダーゼ、SENP5ペプチダーゼ、SENP7ペプチダーゼ、SENP8ペプチダーゼ、SENP4ペプチダーゼ、Poh1ペプチダーゼ、Jab1/MPNドメイン金属酵素、Mername−AA165ペプチダーゼ、Mername−AA166ペプチダーゼ、Mername−AA167ペプチダーゼ、Mername−AA168タンパク質、COP9シグナロソームサブユニット6、26Sプロテアソーム非ATPアーゼ調節サブユニット7、真核細胞翻訳開始因子3サブユニット5、IFP38ペプチダーゼホモログが挙げられる。
本明細書で開示する方法において使用される化合物は、化学式(I):
R3は、アミノアルキレンアリールまたは置換アミノアルキレンアリールであり、
R4は、CN、アミノ、置換アミノ、アミド、置換アミド、アルキレンチオエーテル、置換アルキレンチオエーテル、アルキル、置換アルキル、アジド、アルキレンアジド、および置換アルキレンアジドからなる群から選択され、
R5は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アルコキシ、置換アルコキシ、アルキレンアリール、置換アルキレンアリール、チオエーテル、置換チオエーテル、アミノ、置換アミノ、ハライド、ヒドロキシ、ニトロ、およびSHからなる群から選択され、
R6は、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクロアルケニル、置換ヘテロシクロアルケニル、ヘテロシクロアルキル、置換ヘテロシクロアルキル、アルキレンアリール、置換アルキレンアリール、アルキレンヘテロアリール、置換アルキレンヘテロアリール、アルキレンヘテロシクロアルケニル、置換アルキレンヘテロシクロアルケニル、アルキレンヘテロシクロアルキル、および置換アルキレンヘテロシクロアルキルからなる群から選択される)の化合物またはその塩を含む。
(A)−OH、−NH2、−SH、−CN、−CF3、−NO2、オキソ、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、非置換アルコキシ、非置換アリールオキシ、トリハロメタンスルホニル、トリフルオロメチル、ならびに
(B)以下の(i)および(ii)から選択される少なくとも1個の置換基で置換されたアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、アミノ、アミド、カルボニル、チオカルボニル、アルコキシカルボニル、シリル、スルホニル、スルホキシル、アルコキシ、アリールオキシ、およびヘテロアリール、
(i)−OH、−NH2、−SH、−CN、−CF3、−NO2、オキソ、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、非置換アルコキシ、非置換アリールオキシ、トリハロメタンスルホニル、トリフルオロメチル、および
(ii)以下の(a)および(b)から選択される少なくとも1個の置換基で置換されたアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、アミノ、アミド、カルボニル、チオカルボニル、アルコキシカルボニル、シリル、スルホニル、スルホキシル、アルコキシ、アリールオキシ、およびヘテロアリール、
(a)−OH、−NH2、−SH、−CN、−CF3、−NO2、オキソ、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、非置換アルコキシ、非置換アリールオキシ、トリハロメタンスルホニル、トリフルオロメチル、および
(b)−OH、−NH2、−SH、−CN、−CF3、−NO2、オキソ、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、非置換アルコキシ、非置換アリールオキシ、トリハロメタンスルホニル、トリフルオロメチルから選択される少なくとも1個の置換基で置換されたアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、アミノ、アミド、カルボニル、チオカルボニル、アルコキシカルボニル、シリル、スルホニル、スルホキシル、アルコキシ、アリールオキシ、およびヘテロアリール。
本明細書で開示する方法は、障害を治療する方法、例えば、DUB活性に関連する障害またはDUB活性の調節により影響を受ける障害などを治療する方法、またはDUB活性に関連する障害および/またはDUB活性の調節により影響を受ける障害を治療するための医薬の調製における、本明細書で開示する化合物の使用を含む。さらに考えられるのは、UCH触媒ドメインを阻害することを伴う治療の方法である。考えられる具体的な障害としては、病原性の感染、がん、発達障害および神経変性障害、Riddle症候群、パーキンソン病、アルツハイマー病、およびDUBを要するまたはDUBにより調節される遺伝子障害(例えば、ファンコーニ貧血)が挙げられる。
本明細書で開示する方法および化合物は、病原性の感染の治療において有用であり、例えば、病原性の感染または病原性の感染の症状の予防、抑制および/または緩和において有用である。いくつかの場合において、本明細書で開示する方法および化合物は、病原性の感染による症状の治療において有用である。
本明細書で開示する方法および化合物は、がんの治療、例えば、がんまたはがんの症状の予防、抑制および/または緩和において有用である。いくつかの場合において、がんを治療する上記方法は、DUB(例えば、がんの生存または増殖に関与するDUB)を阻害することを含む。さまざまな場合において、がんを治療するための上記化合物は、WP1130である。
本明細書において使用される用語「治療に有効な量」および「予防に有効な量」は、同定された疾患または症状を治療、緩和または予防するのに十分な化合物の量、または検出可能な治療効果、予防効果または抑制効果を発揮するのに十分な化合物の量を指す。このような効果は、例えば、病態の改善、症状の軽減によって、または本明細書に記載の任意のアッセイまたは臨床診断検査によって検出することができる。対象に対する正確な有効量は、対象の体重、大きさおよび健康、症状の性質および程度、ならびに投与のために選択される治療剤または治療剤の組合せに依存する。所定の状況における治療および予防に有効な量は、臨床医の技量および判断の範囲内である通常の試験により決定することができる。
また、実施形態の方法は、病態を治療するための、本明細書に記載の1以上の化合物と、1以上の別の治療剤との併用を含む。したがって、例えば、併用する活性成分は、(1)1つの製剤とした組合せ製剤として調製し、同時に投与または送達してもよく、(2)別々の製剤として交互でまたは並行して送達してもよく、または(3)当該技術分野で公知の任意の他の組合せ治療レジメンにより送達してもよい。交互療法(alternation therapy)において送達される場合、本明細書に記載の方法は、活性成分を、例えば、別々の液剤、乳剤、懸濁剤、錠剤、丸剤、もしくはカプセル剤として、または別個の注射器に充填した注射剤として、順次投与または送達することを含む。一般に、交互療法においては、各活性成分の有効量を順次(すなわち、連続して)投与するが、同時療法(simultaneous therapy)においては、2以上の活性成分の有効量を一緒に投与する。また、間欠的併用療法をさまざまな順序で使用してもよい。
慢性骨髄性白血病(CML)は、造血幹細胞の染色体異常によって、制御不能なチロシンキナーゼ活性を有するBcr−Ablが発現する疾患である。このような所見は、CML患者に対して顕著な臨床有効性を示した最初のBcr−Ablキナーゼ阻害剤であるイマチニブの開発試験および臨床試験により裏付けられている。イマチニブは、CMLおよびBcr−Ablを発現する他の白血病に対する第一選択の治療薬であり、慢性期にイマチニブを投与された患者の大半において、完全な細胞遺伝学的応答が得られている。しかし、寛解期にイマチニブを投与された患者では、分子学的な検討により、多くの場合Bcr−Ablの発現がなおも検出されること、およびイマチニブ治療を中断すると往々にして再発することが示されている。また、進行したCML患者においてはイマチニブ応答の得られる期間が限定的であることは一般的であり、どのステージにおいてもイマチニブに対する耐性は生じる可能性がある。イマチニブ耐性の獲得および疾患の進行においては、多くの場合、イマチニブの結合およびキナーゼ阻害に影響を及ぼすBcr−Ablの変異および翻訳後修飾が観察されることが特徴である。イマチニブ耐性疾患における分子上の変化は、より高い親和性でBcr−Ablに結合するかまたはイマチニブ耐性に関わるイマチニブ非感受性キナーゼを阻害する第二世代のチロシンキナーゼ阻害剤を用いて克服できるものもある。しかし、これらの阻害剤の活性も、変異などの過程により制限される可能性がある。いくつかの知見により、Bcr−Ablがタンパク質の足場として機能することにより、キナーゼ活性に完全には依存しないシグナル伝達複合体を構成し得ることが示唆されている。このような所見より、場合によっては、Bcr−Ablタンパク質のレベルを調節する化合物の方がCML治療に対して高い有効性や適性を示す可能性があることが示唆される。
ユビキチン化およびユビキチン様タンパク質修飾は、ほとんどの細胞内タンパク質の機能および運命の方向付けに大きな役割を担っている。罹患した細胞では、このような修飾経路における複数の重要な酵素が増幅されるかまたは修飾されていることから、そのような活性を阻害または調節する低分子の開発が行われている。このような修飾経路における特定の酵素を選択的に標的とする方法は大きく進展し、臨床効果を示すものもある。DUBはユビキチンサイクルにおいて特化した役割を有するだけでなく、複数のシグナル伝達経路および発がんタンパク質の制御においてもその役割が新たに発見されていることから、DUB阻害剤は抗がん剤として有用である。WP1130は、ポリユビキチン化タンパク質の蓄積を誘導し、腫瘍細胞のアポトーシスを促進する能力を有することから、有用な抗がん剤として同定されている。
MNVは、初代培養または株化のマウスマクロファージおよびマウス樹状細胞において容易に複製する。MNV侵入阻害剤を同定することを目的として、関与する特定のキナーゼについて調査が進められた結果、Jak2キナーゼ輸送の誘導物質であるWP1130ならびに化学的に関連する化合物WP1051およびWP1052が得られた。
ヒトノロウイルス(ノーウォークウイルスを含む)感染の研究に現在利用できる確立された細胞培養系はない。したがって、細胞におけるNV複製を研究し、取扱いに細心の注意を要するヒトノロウイルスに対する抗ウイルス剤を同定するために、NVレプリコンを有する細胞を開発した。簡単に説明すると、NVのRNAゲノムのcDNAコンセンサス配列(クローニングしたもの)を含有するプラスミドNV101を、主要なカプシドタンパク質であるORF2内にネオマイシン耐性遺伝子をコードするように作製した。得られたプラスミドをpNV−Neoと名付けた。pNV−Neoから得られたRNA転写産物をHuh−7にトランスフェクションした。G418の存在下で生細胞コロニーを選択し、HG23細胞と名付けた。全長ゲノムおよびサブゲノムNV RNA種(センスおよびアンチセンス)の発現ならびに非構造性タンパク質の発現を、ノーザンブロット分析、免疫蛍光アッセイおよびウエスタンブロット分析によりそれぞれ確認した。このレプリコンを有する細胞を用いて、WP1130の抗NV作用について調べた。すなわち、HG23細胞を5μM WP1130で処理して、WP1130のNV複製に対する作用を調べた。この実験において、強力な抗ウイルス性分子であるインターフェロン(IFN)−αを陽性対照として使用した。48時間処理した後に、NVゲノムをqRT−PCRにより分析した。全RNAを調製して定量的リアルタイムPCRに供し、NVゲノムおよびβ−アクチンを検出した。阻害剤によるNVゲノムの減少率は、偽処理(mock−treatment)のものを基準として算出し、次いで、各ゲノムレベルをβ−アクチンレベルで標準化した。WP1130のHG23細胞に対する非特異的な細胞毒性作用は、細胞毒性アッセイキット(AnaSpec、サンノゼ、CA)を用いてモニタした。HG23細胞において、WP1130は5μMで有意な抗NV作用を示し、これはIFNαと同等レベルであった。しかし、10μMより高い濃度では、化合物による細胞毒性がHG23細胞において観察された。このように、WP1130は、抗ウイルス剤が現在利用可能でないマウスノロウイルスおよびヒトノロウイルスに対して抗ウイルス活性を有する。
WP1130がノロウイルスの複製を阻害するというデータに基づき、より広範囲のウイルスに対しても抗ウイルス活性を示すかどうかを調べた。RNAゲノムを有するウイルス群を対象にしたところ、WP1130は脳心筋炎ウイルス(EMCV)、シンドビスウイルス(SiNV)、ラクロスウイルス(LaCV)の感染を阻止し、水疱性口内炎(Vesicular Stomatitis Virus)(VSV)の感染は阻止しないことが分かった。EMCVは、カリシウイルス科(ノロウイルスを含む)に最も近縁のピコルナウイルス科に属する(+)センスRNAウイルスである。シンドビスウイルスは、トガウイルス科(南北アメリカに見られる東部/西部/ベネズエラ馬脳炎ウイルスに関連する科)に属する(+)センスRNAウイルスである。カテゴリーBのラクロスウイルスおよび水疱性口内炎は、それぞれブニヤウイルス科(例えば、ハンタウイルス、リフトバレー熱ウイルス、クリミア・コンゴ出血熱ウイルス)およびラブドウイルス科(例えば、狂犬病ウイルス)に属する(−)センスゲノムを有するRNAウイルスである。ウイルスゲノムの極性がWP1130の有効性を決定づけているようには見えないが、このデータより、WP1130が広い抗ウイルス作用を有することが示された。さらに重要なことに、WP1130は、カテゴリーA(ハンタウイルス、リフトバレー熱ウイルス)、B(東部/西部/ベネズエラ馬脳炎ウイルス)、およびC(狂犬病、クリミア・コンゴ出血熱ウイルス)に属する病原体を含む科のウイルスに対しても活性を有する。
リステリア・モノサイトゲネスは、該細菌で汚染された食品の摂取により死に至る可能性のあるリステリア症を起こすグラム陽性桿状細菌である。リステリア・モノサイトゲネスは、マウスマクロファージ細胞株RAW264.7などの非食細胞および食細胞に感染する通性の細胞内病原体である。細菌は食胞から逃避して細胞内複製を始める。細胞内でこのようなライフサイクルを示すことから、この食物媒介病原体に対するWP1130の有効性について試験を行った。マウスマクロファージをL.モノサイトゲネスに感染させる前にWP1130で前処理するか、または対照として感染後にこの化合物で処理した。RAW264.7細胞を播種し、一晩放置して付着させた。翌日、培養培地を吸引し、5μM WP1130またはDMSOビヒクル対照を含有する培地に置き換えた。プレインキュベーションを37℃で30分間行った後、細胞をL.モノサイトゲネス株10403S(MOI=1)と37℃で30分間接触させて感染させた。細胞をPBSおよび10μg/mlのゲンタマイシンを含有する培地で3回洗浄し、WP1130を細胞に再度加えた。後処理に関しては、感染後1時間経ってからWP1130を加えた。感染から8時間後に、RAW264.7細胞を滅菌水中で溶解し、細菌を増殖培地プレートに接種した。これを37℃で24時間インキュベートした後、コロニー形成単位(CFU)を求めて、ビヒクル対照に対して標準化した。細胞生存率をWST−1(Roche)を用いて測定したところ、80%超を維持していた。細胞をWP1130で前処理すると、ビヒクル対照群または後処理群と比べて、増殖した細菌は有意に少なかった。興味深いことに、感染から1時間後にWP1130で処理した場合は、コロニー形成単位の低下は見られなかった。このことは、この化合物がリステリアのライフサイクルの早い段階で作用していることを示す。これらのデータより、WP1130は、抗ウイルス活性に加えて抗細菌性を有することが分かる。したがって、WP1130は、広いスペクトルを有する抗菌剤として優れた候補化合物であると言える。
トキソプラズマ・ゴンヂは、寄生性原生動物に属する原虫であり、トキソプラズマ症の原因病原体である。トキソプラズマ症を予防および治療する現在の薬物療法は、効果が限定的であるとともに重篤な副作用を引き起こす可能性もある。T・ゴンヂは、ほとんどすべての有核細胞に感染する偏性細胞内病原体である。この寄生体は、タキゾイトとブラディゾイトという2つの形態を有する。半数体であるタキゾイトは、急速に分裂し、可逆的に潜伏性のブラディゾイトとなって、慢性感染の特徴とされる細胞内組織嚢胞を形成する。感染中、トキソプラズマは、寄生体胞(parasitophorous vacuole)と呼ばれる細胞内コンパートメントを形成し、これを宿主細胞の機能を調節するためのプラットホームとして利用する。そこで、WP1130の抗寄生体機能について試験を行った。
RAW264.7細胞またはスイスウェブスター(Swiss Webster)マウス由来の初代培養骨髄由来マクロファージを播種し、一晩放置して付着させた。翌日、培養培地を吸引し、阻害剤(5μM WP1130または5μM WPDTT)またはDMSO(ビヒクル対照)を含有する培地に置き換えた。抗ウイルス作用を有する陽性対照として、IFN−βで細胞を処理した。プレインキュベーションを37℃で30分間行った後、細胞を氷上にてMNV−1(MOI=5)に感染させた。ウイルスを除去し、化合物を再度加え、8または12時間静置した。WPDTTによっても、WP1130と同様にウイルス力価の低下が見られた。
RAW264.7細胞を、MNV−1に感染させる前に、濃度が異なるWP1130で前処理した。感染後12時間の時点で、各濃度におけるウイルス力価および細胞生存率(WST−1生存率アッセイ、Roche)を比較した。抗ウイルス活性を示すEC50は1.9μMと推定され、生存率に対するIC50は7.6μMと推定された。これらの値から治療指数を約4.0と算出した。
RAW264.7細胞を5μM WP1130で2時間処理した後、等量のタンパク質を含有する細胞溶解液(20μg)をSDS−PAGEに供してタンパク質を分離し、抗ユビキチン抗体を用いた免疫ブロット法によりユビキチン化タンパク質のレベルを調べた。RAW264.7細胞を5μM WP1130またはビヒクル単独(対照)とともに2時間インキュベートした後、細胞溶解液を調製し、HA−UbVS(200ng)とともにさらに1時間インキュベートした後、HAブロット法によりDUB活性を検出した。次いで、同じ膜を用いて、Usp9xについてもブロットを行った。その結果、RAW264.7細胞をWP1130でインキュベートすることによりUsp9xが阻害されることが示された。また、HEK293溶解液に対しても、Usp9xについて免疫ブロットを行った。
RAW264.7細胞を非処理のままにするか、または指示濃度のWP1130で2時間処理し、次いで、細胞を偽感染させるか、またはMNV−1に感染させた(MOI=5)。細胞を37℃でさらに2時間インキュベートした後、細胞溶解液を調製し、HA−UbVS(200ng)とともにさらに1時間インキュベートした後、HAブロット法によりDUB活性を検出した。MNV−1感染により、複数種のDUBの活性が増大した。また、抗ウイルス作用を示すのに有効な濃度のWP1130を使用した場合、MNV−1感染によって誘導されるDUB活性が抑制されることが分かった。これより低い濃度のWP1130(1.25μM)は、MNV−1の阻害にも、MNV−1感染に伴うDUB活性化の阻害にも効果的ではなかった。これらの結果より、WP1130の抗ウイルス活性は、MNV−1感染によって誘導されるDUB活性化の阻害に関わることが示唆される。
本明細書で開示する化合物は、熟練した通常の化学者が容易に利用可能な任意の手段によって調製することができる。これらの化合物の一部について合成経路の例を以下のスキームに示す。当業者であれば、これらの合成スキームを容易に改変して本明細書に記載の化合物に到達することができるだろう。
CML、骨髄腫およびマントル細胞リンパ腫の各細胞株を対象として、化合物のDUB阻害活性およびアポトーシス活性の有無をスクリーニングし、WP1130と比較した。選択した化合物による細胞増殖および生存に対する効果をWP1130と比較して表1に示す。例えば、「高感度」な化合物とは、WP1130より高い阻害活性を有する化合物であり、「低感度」な化合物とは、WP1130より低い阻害活性を有する化合物である。また、選択した化合物のDUB阻害の有無についても、細胞(表2)および細胞より分離したDUB(Usp9x−UCHドメイン)酵素調製物(表3)を用いて調べた。これらのアッセイにおいて使用した方法の概要は、例えば、以下の文献に記載されている。Kapuria, et al., A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination, Cell Signal, 2011, in press; Kapuria, et al., Deubiquitinase inhibition by small−molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res, 2010. 70(22): p. 9265−76; Sun, et al., Bcr−Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood, 2011. 117(11): p. 3151−62; Kapuria, et al., Protein cross−linking as a novel mechanism of action of a ubiquitin−activating enzyme inhibitor with anti−tumor activity. Biochem Pharmacol, 2011. 82(4): p. 341−9; and Bartholomeusz, et al., Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood, 2007. 109(8): p. 3470−8.
また、表4に示すように、種々のウイルスに対する、化合物の抗ウイルス作用についても調べた。ノーウォークウイルスのゲノム力価の測定は、レプリコン含有細胞株をWP1130で24時間処理した後、qRT−PCRを実施することにより行った(Chang,Sosnovtsev et al. 2006)。その他の実験は以下のように実施した。細胞を5μMの化合物により37℃で30分間前処理した。細胞へのウイルス感染は氷上で1時間行った。次いで、細胞を洗浄して、未結合のウイルスを除去した。細胞を化合物の存在下でさらに8〜12時間インキュベートした後、ウイルス力価をプラークアッセイにより測定した(Wobus,Karst et al. 2004)。
また、WP1130は、初代培養ヒト包皮線維芽細胞において、アピコンプレックス門(apicomplexan)に属するトキソプラズマ・ゴンヂの複製を阻害する。細胞をWP1130で処理し、タキゾイト(RH株)(MOI=1)に24時間感染させた後、免疫蛍光法を用いて寄生体含有液胞を計数した。寄生体を1個のみ含有する液胞数は約3倍に増加し、寄生体を4個含有する液胞数は約5分の1に減少した。
RAW264.7マクロファージを5μM WP1130で処理したところ、感染後8時間の間にリステリア・モノサイトゲネスの力価は3〜10分の1に低下した。力価は、細胞内のコロニー形成単位を経時的に測定することにより求めた。上記マクロファージと接種細菌との接触は、MOI=1で30分間行った。WP1130処理および感染の前にリポ多糖類およびインターフェロン−γで活性化した初代培養骨髄由来マクロファージにおいても、同様の効果が観察された。またWP1130処理によって、感染後8時間の間にRAW264.7マクロファージ内のメチシリン耐性黄色ブドウ球菌(MRSA)の生存は3〜4分の1に低下した。また、この効果は、MRSAに感染したヒト子宮頸管上皮HeLa細胞においても観察された。RAW264.7細胞において33および40を使用した場合にも、同様の細菌生存の低下がMRSAにおいて見られた。
Claims (40)
- 化学式(II)もしくは(IIa):
R 1A は、H、アミド、置換アミド、ハライド、−(CH2)mR9、−NH(CH2)mR9、−NHC(O)(CH2)mR9、−C(O)NH(CH2)mR9および−O(CH2)mR9からなる群から選択され、
Xは、フルオロまたはクロロであり、
R2は、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アリール、置換アリール、ヘテロアリール、または置換ヘテロアリールであり、
R9は、アミノ、置換アミノ、ヒドロキシ、アルコキシ、置換アルコキシ、シクロヘテロアルキル、または置換シクロヘテロアルキルであり、
mは、2、3、または4である)を有する化合物またはその塩。 - R2が、ヒドロキシ、アミノ、置換アミノ、アルコキシおよび置換アルコキシのうちの1以上で所望により置換されていてもよいC1−6アルキルまたはC3−6シクロアルキルである、請求項1に記載の化合物。
- R 1A が、−O(CH2)mNEt2、−O(CH2)mNMe2、−O(CH2)mNHEt、−O(CH2)mNHMe、−O(CH2)mモルホリニル、−O(CH2)m置換モルホリニル、−O(CH2)mスルホキシモルホリニル、−O(CH2)m置換スルホキシモルホリニル、−O(CH2)mピロリジニル、−O(CH2)m置換ピロリジニル、−O(CH2)mピペラジニル、−O(CH2)m置換ピペラジニル、−O(CH2)mピペリジニル、−O(CH2)m置換ピペリジニル、−O(CH2)mN(Me)(CH2)2NMe2、−O(CH2)mN(Me)(CH2)2NHMe、−O(CH2)mN(Me)(CH2)2NEt2、−O(CH2)mN(Me)(CH2)2NHEt、−O(CH2)mO(CH2)2NMe2、−O(CH2)mO(CH2)2NHMe、−O(CH2)mO(CH2)2NEt2、−O(CH2)mO(CH2)2NHEt、−O(CH2)mO(CH2)2ヘテロシクロアルキル、および−O(CH2)mO(CH2)2置換ヘテロシクロアルキルからなる群から選択される、請求項1または2に記載の化合物。
- R9が、OH、NH2、NHMe、N(Me)2、N(Et)2、O(CH2)2NH2、NH(CH2)2OH、N(Me)(CH2)2N(Me2)、
- R 1A が、H、アミド、置換アミドおよびハライドからなる群から選択される、請求項1に記載の化合物。
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からなる群から選択される化合物またはその塩。 - 請求項1〜7のいずれか1項に記載の化合物と薬学的に許容可能な担体とを含む医薬組成物。
- 経口投与、局所投与、静脈内投与、皮下投与、筋肉内投与、クモ膜腔内投与、眼内投与または吸入投与に適した、請求項8に記載の医薬組成物。
- 細胞の増殖を抑制する医薬製造のための請求項1〜7のいずれか1項に記載の化合物の使用。
- 前記細胞ががん細胞である、請求項10に記載の使用。
- 前記がん細胞が、ウイルス誘発性がん、カポジ肉腫、鼻咽頭癌腫(EBV)、慢性骨髄性白血病(CML)、黒色腫、急性リンパ性白血病、慢性リンパ性白血病、急性骨髄性白血病、B細胞リンパ腫、マントル細胞リンパ腫、多発性骨髄腫、形質細胞異形成、骨髄増殖性障害または膠芽腫である、請求項11に記載の使用。
- 前記がんが、肺がん、乳がん、前立腺がん、膵臓がん、固形腫瘍または結腸がんである、請求項11に記載の使用。
- 前記化合物が前記細胞の内因性の脱ユビキチン化酵素(DUB)を阻害する、請求項10〜13のいずれか1項に記載の使用。
- 前記化合物がDUBのユビキチンC末端加水分解酵素(UCH)触媒ドメインを阻害する、請求項10〜14のいずれか1項に記載の使用。
- 病原性の感染を抑制する医薬製造のための請求項1〜7のいずれか1項に記載の化合物の使用。
- 病原体に感染した細胞を請求項1〜7のいずれか1項に記載の化合物と接触させることを特徴とする、病原性の感染による症状を治療する医薬製造のための請求項1〜7のいずれか1項に記載の化合物の使用。
- 前記症状が、胃腸炎、脳炎、気道感染、SARS、インフルエンザ、ウイルス誘発性がん、狂犬病、出血熱、リフトバレー熱、リステリア症およびトキソプラズマ症から選択される、請求項17に記載の使用。
- 前記症状が、髄膜炎、心筋炎、肝炎、菌血症または皮膚感染である、請求項17に記載の使用。
- 前記病原体が、ウイルス、細菌、真菌または寄生体である、請求項16〜19のいずれか1項に記載の使用。
- 前記ウイルスが、カリシウイルス、ノロウイルス、サポウイルス、ピコルナウイルス、トガウイルス、ブニヤウイルス、ラブドウイルス、ヘルペスウイルス、アデノウイルス、アルテリウイルス、コロナウイルス、フラビウイルス、パラミクソウイルス、パピローマウイルス、卵巣腫瘍(OTU)様プロテアーゼをコードするウイルス、バキュロウイルスまたはナイロウイルスである、請求項20に記載の使用。
- 前記ウイルスがポリオーマウイルスまたはレトロウイルスである、請求項20に記載の使用。
- 前記ウイルスが、脳心筋炎ウイルス(EMCV)、シンドビスウイルス(SiNV)、ラクロスウイルス(LaCV)、ノーウォークウイルス、エプスタイン・バール(EBV)、ヘルペスウイルス、デングウイルス、呼吸器系合胞体ウイルス(RSV)、パピローマウイルスおよびインフルエンザからなる群から選択される、請求項20または21に記載の使用。
- 前記ウイルスが、サイトメガロウイルス、BKウイルス、C型肝炎ウイルスまたはHIVである、請求項20または21に記載の使用。
- 前記細菌が、クラミジア、エシェリヒア、サルモネラ、イェルシニア、バークホルデリア、ヘモフィルス、リステリアおよびマイコバクテリウムからなる群から選択される、請求項20に記載の使用。
- 前記細菌が黄色ブドウ球菌である、請求項20に記載の使用。
- 前記細菌がメチシリン耐性黄色ブドウ球菌(MRSA)である、請求項26に記載の使用。
- 前記寄生体または真菌が、熱帯熱マラリア原虫(Plasmodium falciparum)、トキソプラズマ・ゴンヂ(Toxoplasma gondii)、エントアメーバヒストリティカ(Entamoeba histolytica)、ランブル鞭毛虫(Giardia lamblia)、ブルーストリパノソーマ(Trypanosoma brucei)、クルーズトリパノソーマ(Trypanosoma cruzi)、セストダ(Cestoda)、クロノルキス(Clonorchis)、オピストルキス(Opisthorchis)、ストロンギロイデス(Strongylocides)、カンジダ(Candida)、アスペルギルス(Aspergillus)およびクリプトコックス(Cryptococcus)からなる群から選択される、請求項20に記載の使用。
- 前記化合物が脱ユビキチン化酵素(Dub)を阻害する、請求項16〜28のいずれか1項に記載の使用。
- 前記脱ユビキチン化酵素が前記病原体の内因性の脱ユビキチン化酵素である、請求項29に記載の使用。
- 前記脱ユビキチン化酵素が前記細胞の内因性の脱ユビキチン化酵素である、請求項29に記載の使用。
- 前記細胞が哺乳類の細胞である、請求項16〜31のいずれか1項に記載の使用。
- 前記細胞がヒトの細胞である、請求項32に記載の使用。
- 前記細胞が動物の細胞である、請求項16〜31のいずれか1項に記載の使用。
- 前記細胞が鳥類の細胞である、請求項34に記載の使用。
- 神経変性疾患を治療する医薬製造のための請求項1〜7のいずれか1項に記載の化合物の使用。
- 神経変性疾患に伴う1以上の症状を治療する医薬製造のための請求項1〜7のいずれか1項に記載の化合物の使用。
- 遺伝子疾患に伴う1以上の症状を治療する医薬製造のための請求項1〜7のいずれか1項に記載の化合物の使用。
- R 1A が、−(CH 2 ) m R 9 、−NH(CH 2 ) m R 9 、−NHC(O)(CH 2 ) m R 9 、−C(O)NH(CH 2 ) m R 9 および−O(CH 2 ) m R 9 からなる群から選択される、請求項1に記載の化合物。
- R 1A が、ハライドである、請求項1に記載の化合物。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |