JP2017502032A - ダウン症を治療するための細胞内塩化物濃度のモジュレータ - Google Patents
ダウン症を治療するための細胞内塩化物濃度のモジュレータ Download PDFInfo
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- JP2017502032A JP2017502032A JP2016541508A JP2016541508A JP2017502032A JP 2017502032 A JP2017502032 A JP 2017502032A JP 2016541508 A JP2016541508 A JP 2016541508A JP 2016541508 A JP2016541508 A JP 2016541508A JP 2017502032 A JP2017502032 A JP 2017502032A
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- Prior art keywords
- modulator
- chloride
- transporter
- inhibitor
- bumetanide
- Prior art date
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
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- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
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Abstract
Description
本発明において、次の用語は以下の意味を有する。
−「治療」とは治療療法および予防方法の両方のことを指し、その目的は標的となる病態または疾患を予防するまたは疾患の進行を遅らせる(軽減する)ことである。治療が必要な人々はすでに疾患を有する人々だけでなく疾患を有しがちな人々、または疾患の予防ができている人々を含む。有効量の本発明のモジュレータを投与後、患者に目に見えるおよび/または測定可能な1以上のこと、すなわちダウン症に関連する症状が減少したり無くなったり、生活の質に関する問題の改善が見られたら、患者は首尾よく治療されている。首尾よい治療および病気の改善を評価するための上記パラメータは医師によく知られた、決まった手順によって容易に測定することができる。
−1実施形態では、「健康な患者」という用語はダウン症と診断されていない患者を指す。1実施形態では「健康な患者」はダウン症の症状および/または臨床徴候を示さない。
−「阻害剤」とは遺伝子および/またはタンパク質の発現を阻害または有意に低下させるまたは下方制御する、もしくはタンパク質の生物学的活性を阻害または有意に低下させる生物学的効果を有する天然または合成化合物を指す。それ故に「NKCC阻害剤」とはNKCCをコードする遺伝子の発現および/またはNKCCタンパク質の発現および/またはNKCCの生物学的活性を阻害または有意に低下させる生物学的効果を有する天然または合成化合物を指す。
−「類似体」とは、おおまかには親化合物上の1以上の化学的部分の修飾または置換のことを指し、機能的誘導体、位置異性体、互変異性体、両性イオン、光学異性体、ジアステレオマー、ラセミ化合物、イソスターまたはその立体化学的混合物を挙げることができる。
−「機能性誘導体」とは、ニューロンに流入する塩化物濃度を調節する(塩化物の移入を阻害するまたは塩化物の流出を活性化する)能力を持つ化合物を指す。
本発明の阻害剤はイソスターも含むことができる。
ピレタニドモルホリノエチルエステル、ピレタニド3−(ジメチルアミノプロピル)エステル、ピレタニドN,N−ジエチルグリコールアミドエステル、ピレタニドジエチルアミド、ピレタニドジベンジルアミド、ピレタニドジエチルアミド、ピレタニドジベンジルアミド、ピレタニドベンジルトリメチルアンモニウム塩、ピレタニドセチルトリメチルアンモニウム塩、ピレタニドN,N−ジメチルグリコールアミドエステル、ピレタニドメトキシ(ポリエチレンオキシ)n−1−エチルエステル、ピレタニドピバキセチルエステル、ピレタニドプロパキセチルエステル、ピレタニド[−(C=O)−SH]チオ酸、ピレタニドS−メチルチオエステル、ピレタニドS−シアノメチルチオエステル、ピレタニドS−エチルチオエステル、ピレタニドS−イソアミルチオエステル、ピレタニドS−オクチルチオエステル、ピレタニドS−ベンジルチオエステル、ピレタニドS−(モルホリノエチル)チオエステル、ピレタニドS−[3−(ジメチルアミノプロピル)]チオエステル、ピレタニドS−(N,N−ジエチルグリコールアミド)チオエステル、ピレタニドS−(N,N−ジメチルグリコールアミド)チオエステル、ピレタニドS−ピバキセチルチオエステル、ピレタニドS−プロパキセチルチオエステル、ピレタニドS−[メトキシ(ポリエチレンオキシ)n−1−エチル]チオエステル、ピレタニド[−(C=O)−S−]ベンジルトリメチルアンモニウムチオ酸塩、およびピレタニド[−(C=O)−S−]セチルトリメチルアンモニウムチオ酸塩、準安定ピレタニド[−(C=S)−OH]チオ酸、ピレタニドO−メチルチオエステル、ピレタニドO−シアノメチルチオエステル、ピレタニドO−エチルチオエステル、ピレタニドO−イソアミルチオエステル、ピレタニドO−オクチルチオエステル、ピレタニドO−ベンジルチオエステル、ピレタニドO−(モルホリノエチル)チオエステル、ピレタニドO−[3−(ジメチルアミノプロピル)]チオエステル、ピレタニドO−(N,N−ジエチルグリコールアミド)チオエステル、ピレタニドO−(N,N−ジメチルグリコールアミド)チオエステル、ピレタニドO−ピバキセチルチオエステル、ピレタニドO−プロパキセチルチオエステル、ピレタニドO−[メトキシ(ポリエチレンオキシ)n−1−エチル]チオエステル、ピレタニド[−(C=S)−O−]ベンジルトリメチルアンモニウムチオ酸塩、およびピレタニド[−(C=S)−O−]セチルトリメチルアンモニウムチオ酸塩、ピレタニドチオアルデヒド、ピレタニド[−(C=S)−SH]ジチオ酸、ピレタニドメチルジチオエステル、ピレタニドシアノメチルジチオエステル、ピレタニドエチルジチオエステル、ピレタニドイソアミルジチオエステル、ピレタニドオクチルジチオエステル、ピレタニドベンジルジチオエステル、ピレタニドジベンジルチオアミド、ピレタニドジエチルチオアミド、ピレタニドモルホリノエチルジチオエステル、ピレタニド3−(ジメチルアミノプロピル)ジチオエステル、ピレタニドN,N−ジエチルグリコールアミドジチオエステル、ピレタニドN,N−ジメチルグリコールアミドジチオエステル、ピレタニドピバキセチルジチオエステル、ピレタニドプロパキセチルジチオエステル、ピレタニドメトキシポリエチレンオキシエチルジチオエステル、ピレタニドベンジルトリメチルアンモニウムジチオ酸塩、およびピレタニドセチルトリメチルアンモニウムジチオ酸塩が挙げられるが、これらに限定されない。
式中、
−R1は存在しない、またはHもしくはOであり、
−R2はHまたはR1がOである場合、非置換又は置換アルキルアミノジアルキル、アルキルアミノカルボニルジアルキル、アルキルオキシカルボニルアルキル、アルキルアルデヒド、アルキルケトアルキル、アルキルアミド、アルキルアンモニウム基、アルキルカルボン酸、アルキルヘテロアリール、アルキルヒドロキシ、アルキルオキシ(ポリアルキルオキシ)アルキルヒドロキシル、ポリエチレングリコール(PEG)、ポリエチレングリコールエステル(PEGエステル)、ポリエチレングリコールエーテル(PEGエーテル)、メチルオキシアルキル、メチルオキシアルカリル、メチルチオアルキルアルキルおよびメチルチオアルカリル等の生体適合性ポリマーからなる群より選択され、R1が存在しない場合、R2は水素、非置換又は置換ジアルキルアミノ、ジアリールアミノ、ジアルキルアミノジアルキル、ジアルキルカルボニルアミドジアルキル、ジアルキルエステルアルキル、ジアルキルアルデヒド、ジアルキルケトアルキル、ジアルキルアミド、ジアルキルカルボン酸、およびジアルキルへテロアリールのからなる群より選択され、
−R3は非置換又は置換アリール、ハロ、ヒドロキシ、アルコキシ及びアリールオキシからなる群より選択され、
−R4及びR5は各々独立して水素、非置換又は置換アルキルアミノジアルキル、アルキルヒドロキシアミノジアルキルからなる群より選択される。
式中、
−R3、R4およびR5は上記で定義したとおりであり、
−R6は非置換または置換アルキルオキシカルボニルアルキル、アルキルアミノカルボニルジアルキル、アルキルアミノジアルキル、アルキルヒドロキシ、アルキルオキシ(ポリアルキルオキシ)アルキルヒドロキシル、ポリエチレングリコール(PEG)、ポリエチレングリコールエステル(PEGエステル)、およびポリエチレングリコールエーテル(PEGエーテル)等の生体適合性ポリマー、メチルオキシアルキル、メチルオキシアルカリル、メチルチオアルキルおよびメチルチオアルカリルからなる群より選択される。
式中、
R7は非置換又は置換アルキルオキシカルボニルアルキル、アルキルアミノカルボニルジアルキル、アルキルアミノジアルキル、アルキルヒドロキシ、アルキルオキシ(ポリアルキルオキシ)アルキルヒドロキシル、ポリエチレングリコール(PEG)、ポリエチレングリコールエステル(PEGエステル)、ポリエチレングリコールエーテル(PEGエーテル)、メチルチオアルキルおよびメチルチオアルカリル等の生体適合性ポリマーからなる群より選択され、X−は臭化物、塩化物、フッ化物、ヨウ化物などのハロゲン化物またはメシラートまたはトシレートなどのアニオン部分であり、あるいは、Xは存在せず、化合物はスルホニル尿素部分(−SO2−NH−CO−)から陽子が消失することにより「内」塩または両性イオン塩を形成する。
式中
−Zは酸素または窒素であり、
−R1およびR2はそれぞれ独立して水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテリアリールアルキル、ヘテロシクロアルキル、またはR1およびR2はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成するが、Zが酸素の場合、R2は存在せず、
−R3およびR4はそれぞれ独立して水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、もしくはヘテロアリールアルキル、またはR3およびR4はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成し、
−R5はハロ、アリール、アリールオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、またはアルキルチオであり、
−R6およびR7はそれぞれ独立して水素、アシル、アルキル、シクロアルキルアルキル、アリールもしくはアリールオキシ、またはR6およびR7はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成する。
式中
−Zは酸素または窒素であり、
−R1およびR2はそれぞれ独立して水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキル、またはR1およびR2はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成するが、Zが酸素の場合、R2は存在しない、
−R3およびR4はそれぞれ独立して水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、もしくはヘテロアリールアルキル、またはR3およびR4はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成し、
−R5はアルコキシ、ハロ、アリール、アリールオキシ、アルカリルオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、ヘテロアリール、ヘテロアリールオキシ、ヘテロシクロアルコキシ、またはアルキルチオであり、
−R6およびR7はそれぞれ独立して水素、アシル、アルキル、シクロアルキルアルキル、アリールもしくはアリールオキシ、またはR6およびR7はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成し、
−R8およびR9はそれぞれ独立して水素、アルキル、またはR8およびR9はそれらが結合した原子と共に置換または非置換の3−6員シクロアルキルまたはヘテロシクロアルキル環を形成する。
式中
−Zは酸素または窒素であり、
−R1およびR2はそれぞれ独立して水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキル、またはR1およびR2はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成するが、Zが酸素の場合、R2は存在せず、
−R3およびR4はそれぞれ独立して水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、もしくはヘテロアリールアルキル、またはR3およびR4はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成し、
−R5はアルコキシ、ハロ、アリール、アリールオキシ、アルカリルオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、ヘテロアリール、ヘテロアリールオキシ、ヘテロシクロアルコキシ、またはアルキルチオであり、
−R6およびR7はそれぞれ独立して水素、アシル、アルキル、シクロアルキルアルキル、アリール、もしくはアリールオキシ、またはR6およびR7はそれらが結合した原子と共に1以上の付加的なヘテロ原子を有していてもよく1以上の置換基を有していてもよい4−7員環を形成し、
−R8およびR9はそれぞれ独立して水素、アルキル、またはR8およびR9はそれらが結合した原子と共に置換または非置換の3−6員シクロアルキルまたはヘテロシクロアルキル環を形成する。
することができる。
実施例
材料および方法
動物
大部分のヒト第21染色体の長腕に相同なマウス第16染色体の一部の分節重複を有するダウン症のマウスモデル、Ts65Dnマウスは学習および記憶障害を示すが、これらは仮定上では神経構造の全体的な異常よりもむしろ脳中の興奮性シナプスの選択的減少が原因である。理論的には、Ts65Dnマウスに見られる3重遺伝子によって、歯状回(および、場合によっては脳の他の部分)における興奮と抑制の最適バランスが、過度の抑制によって正常な学習および記憶を混乱させる状態へと移行する(Reeves et al., Nature Genetics, 11(2):177-84 (1995))。
統計
すべてのパネルに関して、ヒストグラムは平均プラスマイナス標準誤差を表し、円は単一細胞からのデータを意味する。統計学的有意性:*P<0.05、**P<0.01、***P<0.001
Claims (24)
- ダウン症の治療に用いる塩化物輸送体のモジュレータ。
- 前記モジュレータは塩化物のニューロンへの移入に関与する輸送体の阻害剤であることを特徴とする請求項1記載の使用のための塩化物輸送体のモジュレータ。
- 前記モジュレータは塩化物のニューロンへの移入に関与する輸送体の発現の阻害剤であることを特徴とする請求項1記載の使用のための塩化物輸送体のモジュレータ。
- 塩化物のニューロンへの移入に関与する塩化物輸送体のsiRNA、shRNA、アンチセンス・オリゴヌクレオチド、リボザイムおよびアプタマーからなる群から選択されることを特徴とする請求項3記載の使用のための塩化物輸送体のモジュレータ。
- 前記モジュレータは塩化物のニューロンへの移入に関与する輸送体の活性の阻害剤であることを特徴とする請求項1記載の使用のための塩化物輸送体のモジュレータ。
- 前記モジュレータは輸送体NKCCの阻害剤であることを特徴とする請求項1記載の使用のための塩化物輸送体のモジュレータ。
- 前記輸送体NKCCの阻害剤はブメタニド、フロセミド、エタクリン酸、トルセミド、アゾセミド、ムゾリミン、ピレタニド、トリパミドおよびその類似体、機能性誘導体および/またはプロドラッグ、ベンドロフルメチアジド、ベンズチアジド、クロロチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、メチルクロチアジド、ポリチアジド、トリクロロメチアジド、クロロタリドン、インダパミド、メトラゾンおよびキネタゾンなどのチアジドおよびチアジド系利尿薬、その類似体および/または機能性誘導体および/またはプロドラッグからなる群から選択されることを特徴とする請求項6記載の使用のための塩化物輸送体のモジュレータ。
- 前記輸送体NKCCの阻害剤がブメタニドであることを特徴とする請求項7記載の使用のための塩化物輸送体のモジュレータ。
- 前記治療は有効量の前記モジュレータの投与を必要とする患者への該モジュレータの投与を含み、前記有効量は約0.01mgから約500mgであることを特徴とする請求項1から8のいずれか一項記載の使用のための塩化物輸送体のモジュレータ。
- 前記塩化物輸送体のモジュレータは皮下、筋肉内、静脈内、眼球内、経皮、局所、非経口、鼻腔内もしくは経口投与、または注入によって該モジュレータの投与を必要とする患者に直接投与されることを特徴とする請求項9記載の使用のための塩化物輸送体のモジュレータ。
- 患者はダウン症と診断されていることを特徴とする請求項1から10のいずれか一項記載の使用のための塩化物輸送体のモジュレータ。
- 患者はダウン症にかかっていることを特徴とする請求項1から11のいずれか一項記載の使用のための塩化物輸送体のモジュレータ。
- ダウン症を示す患者を治療する方法であって、前記方法は有効量の塩化物輸送体のモジュレータの投与を含むことを特徴とする方法。
- 前記モジュレータは塩化物のニューロンへの移入に関与する輸送体の阻害剤であることを特徴とする請求項13記載の方法。
- 前記モジュレータは塩化物のニューロンへの移入に関与する輸送体の発現の阻害剤であることを特徴とする請求項13記載の方法。
- 前記モジュレータは塩化物のニューロンへの移入に関与する塩化物輸送体のsiRNA、shRNA、アンチセンス・オリゴヌクレオチド、リボザイムおよびアプタマーからなる群から選択されることを特徴とする請求項15記載の方法。
- 前記モジュレータは塩化物のニューロンへの移入に関与する輸送体の活性の阻害剤であることを特徴とする請求項13記載の方法。
- 前記モジュレータは輸送体NKCCの阻害剤であることを特徴とする請求項17記載の方法。
- 前記輸送体NKCCの阻害剤はブメタニド、フロセミド、エタクリン酸、トルセミド、アゾセミド、ムゾリミン、ピレタニド、トリパミドおよびその類似体、機能性誘導体および/またはプロドラッグ、ベンドロフルメチアジド、ベンズチアジド、クロロチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、メチルクロチアジド、ポリチアジド、トリクロロメチアジド、クロロタリドン、インダパミド、メトラゾンおよびキネタゾンなどのチアジドおよびチアジド系利尿薬、その類似体および/または機能性誘導体および/またはプロドラッグからなる群から選択されることを特徴とする請求項18記載の方法。
- 前記輸送体NKCCの阻害剤がブメタニドであることを特徴とする請求項19に記載の方法。
- 前記有効量は約0.01mgから約500mgであることを特徴とする請求項13記載の方法。
- 前記塩化物輸送体のモジュレータは皮下、筋肉内、静脈内、眼球内、経皮、局所、非経口、鼻腔内または経口投与、もしくは注入によって該モジュレータの投与を必要とする患者に直接投与されることを特徴とする請求項13記載の方法。
- 患者はダウン症と診断されていることを特徴とする請求項13記載の方法。
- 患者はダウン症にかかっていることを特徴とする請求項13記載の方法。
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