JP2012502111A - アリールグアニジンf1f0−atpアーゼ阻害剤およびそれと関連する方法 - Google Patents
アリールグアニジンf1f0−atpアーゼ阻害剤およびそれと関連する方法 Download PDFInfo
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- JP2012502111A JP2012502111A JP2011526999A JP2011526999A JP2012502111A JP 2012502111 A JP2012502111 A JP 2012502111A JP 2011526999 A JP2011526999 A JP 2011526999A JP 2011526999 A JP2011526999 A JP 2011526999A JP 2012502111 A JP2012502111 A JP 2012502111A
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- alkyl
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- halogen
- haloalkyl
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Abstract
Description
関連出願
本出願は、その内容を参照によって本明細書に援用する、2008年9月11日に出願された米国仮特許出願第61/096,184号明細書に対する優先権の利益を主張するものである。
多細胞生物は細胞数を正確に制御している。このホメオスタシスは、細胞増殖と細胞死とのバランスにより達成される。細胞死は、壊死により、あるいは、アポトーシスと呼ばれる自殺型の細胞死によりほぼすべての種類の脊椎動物細胞で起こる。アポトーシスは、遺伝的にプログラムされた共通の死機構に関与する様々な細胞外および細胞内シグナルによって引き起こされる。
本発明は、F1F0−ATPアーゼ(たとえば、ミトコンドリアF1F0−ATPアーゼ)の阻害剤、F1F0−ATPアーゼの阻害剤を発見する方法、およびそうした阻害剤を用いて種々の状態を処置する方法を提供する。
本発明を理解しやすくするため、以下にいくつかの用語および語句を定義する。
本発明は、F1F0−ATPアーゼ(たとえば、ミトコンドリアF1F0−ATPアーゼ)の阻害剤、その発見方法、およびその治療用途に関する。特に、本発明は、F1F0−ATPアーゼ阻害剤として有用な一連のグアニジン化合物、およびこうした化合物を治療薬として使用して多くの様々な状態を処置する方法を提供する。
いくつかの実施形態では、本発明は、細胞を本発明の化合物に曝露することによりF1F0−ATPアーゼ活性(たとえば、ミトコンドリアF1F0−ATPアーゼ活性)を調節する。いくつかの実施形態では、本化合物は、ATP合成およびATP加水分解を阻害する。化合物の作用については、何らかの細胞の変化を検出することにより測定することができる。たとえば、本明細書および当該技術分野に記載されるようにミトコンドリアF1F0−ATPアーゼ活性および/または細胞死を評価してもよい。いくつかの実施形態では、細胞株を適切な細胞培養条件(たとえば、ガス(CO2)、温度および培地)下、適切な期間維持して密度依存性の制約を受けない指数関数的な増殖を達成する。細胞の数およびまたは生存率は、トリパンブルー排除/血球計算法またはMTT色素変換アッセイなどの標準的な技法を用いて測定する。あるいは、細胞について、アポトーシスまたは壊死の異常に関連する遺伝子または遺伝子産物の発現を解析してもよい。
一態様では、本発明は、下記式Iで表される化合物であって:
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物である、一連の化合物を提供する。
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、一連の化合物を提供する。
式IおよびIIのグアニジン化合物とこれに関連するグアニジンを用いた化合物は、たとえば、F1F0−ATPアーゼ活性の調節不全を特徴とする疾患、細胞または組織内の壊死および/またはアポトーシス過程の調節不全を特徴とする疾患、異常な細胞増殖および/または過剰増殖を特徴とする疾患など多くの状態の任意の1つまたは複数に罹患している患者に治療効果を与えることを意図している。本明細書に記載の化合物はまた、本明細書の別の箇所で記載したような細胞の死に関連する様々な調節不全障害を処置するのに使用してもよい。加えて、本明細書に記載の化合物は、ATP合成および加水分解の両方を阻害するのに使用してもよい。
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり;
式IIは下記式で表され:
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、方法を提供する。
以下、検討された種々の薬物および医薬組成物の例示的な実施形態について記載する。
本発明の化合物は、細胞死の調節不全、異常な細胞増殖および過剰増殖に関連する様々な状態を処置したり、あるいは研究したりする薬物の調製に有用である。
本発明のいくつかの実施形態では、本組成物を単独投与するのに対し、いくつかの他の実施形態では、本組成物は、好ましくは固体支持体と共に、あるいは、1種または複数種の薬学的に許容されるキャリアおよび任意選択として他の治療薬(たとえば、本明細書の上記セクションIIIにされた治療薬)と共に、上記で論じたような少なくとも1種の活性成分/薬を含む医薬製剤中に存在する。各キャリアは、製剤の他の成分との適合性があり、被検体に有害でないという意味で「許容可能な」ものなければならない。
たとえば、リポソーム、微小粒子、マイクロカプセルへの封入、受容体を介したエンドサイトーシスおよび同種のものなど種々の送達系が知られており、これを利用して本発明の治療薬(たとえば、上記のような例示的な化合物)を投与することができる。送達の方法としては、動脈内経路、筋肉内経路、静脈内経路、鼻腔内経路および経口経路があるが、これに限定されるものではない。特定の実施形態では、処置を必要とする領域に本発明の医薬組成物を局所投与することが望ましい場合があり、これは、たとえば、以下に限定されるものではないが、術中の局所注入、注射、あるいは、カテーテルにより達成することができる。
本発明はさらに、本明細書に記載の化合物と1種または複数種の他の有効成分との併用投与に関する方法も含む。実際、本発明の化合物を併用投与することにより従来技術の治療剤および/または医薬組成物を改良する方法を提供することは、本発明のさらなる態様である。併用投与の手順では、本薬を同時投与しても、または連続的に投与しもよい。一実施形態では、他の有効成分の前に本明細書に記載の化合物を投与する。本医薬製剤および投与モードは、上述のもののいずれであってもよい。さらに、併用投与する2種以上の化学薬品、生物学的治療薬または放射線は各々、異なるモードまたは異なる製剤を用いて投与してもよい。
いくつかの態様では、本発明の化合物および有用性が期待される他の化合物について、F1F0−ATPアーゼのオリゴマイシン感受性付与タンパク質(OSCP)部分(または他の部分)に対するその結合親和性、および/または、F1F0−ATPアーゼ活性またはそれに関連する生物学的プロセスを変化させる能力をスクリーニングする。特に好ましい実施形態では、組換えOSCPタンパク質に対するその結合親和性を測定して本発明の方法に使用する化合物を選択する。受容体に対する薬剤および他の小分子の結合親和性を測定するための多くの好適なスクリーニングが当該技術分野において公知である。いくつかの実施形態では、結合親和性スクリーニングをインビトロ系で行う。他の実施形態では、こうしたスクリーニングをインビボまたはエキソビボ系で行う。いくつかの実施形態では本発明の化合物を投与後に細胞内のATPのレベルを定量して本方法の有効性の指標とするのに対し、本発明の好ましい実施形態では細胞内のATPまたはpHレベルを定量する必要はない。
本発明を全般的に記載してきたが、次に以下の実施例を参照すれば、本発明がさらに理解しやすくなるであろう。実施例は、本発明のある種の態様および実施形態の説明のみを目的として記載するものであり、本発明を限定することを意図するものではない。
グアニジンを調製する一般的な手順。
方法A:
チオ尿素を調製するための代表的な手順。
方法B:
表VIIに記載した化合物についてRamos細胞の細胞毒性を試験した。アッセイについては、K.M.Johnson et al.Chemistry & Biology 2005,12,485−496に記載されているように行った。
本明細書に記載した特許文書および科学論文はそれぞれ、あらゆる面で開示内容全体を参照によって援用する。
本発明は、その精神または本質的な特徴を逸脱することなく他の特定の形態で実施してもよい。したがって、上記の実施形態は、あらゆる点で例示と解釈すべきものであり、本明細書に記載の本発明を限定するものではない。このため、本発明の範囲は、明細書本文ではなく添付の特許請求の範囲により示されるものであり、さらに特許請求の範囲の均等範囲に属する変更はすべて、特許請求の範囲に包含されるものとする。
Claims (60)
- 下記式Iで表される化合物であって:
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物である、
化合物。 - X1は−N(R2)−であり、X2は−N(H)−、−N(アルキル)−または−N(ヒドロキシアルキル)−である、請求項5に記載の化合物。
- X1は−N(R2)−であり、X2はOである、請求項5に記載の化合物。
- X1は−N(R2)−であり、X2は−C(H)(アルキル)−である、請求項5に記載の化合物。
- R2およびR3は水素である、請求項1〜8のいずれか1項に記載の化合物。
- R7はアルキルまたはハロアルキルである、請求項1〜10のいずれか1項に記載の化合物。
- R8は水素、ハロゲンまたはアルキルである、請求項1〜11のいずれか1項に記載の化合物。
- mは1である、請求項1〜12のいずれか1項に記載の化合物。
- R5はハロゲンである、請求項1〜13のいずれか1項に記載の化合物。
- nは0、1または2である、請求項1〜14のいずれか1項に記載の化合物。
- 下記式IIで表される化合物であって:
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、
化合物。 - R1、R2およびR3は水素である、請求項17に記載の化合物。
- R5はハロゲンである、請求項17〜22のいずれか1項に記載の化合物。
- nは1、2または3である、請求項17〜23のいずれか1項に記載の化合物。
- mは1である、請求項17〜24のいずれか1項に記載の化合物。
- 前記化合物は表I〜Vに記載した化合物の1つである、請求項1または17に記載の化合物。
- 請求項1〜27のいずれか1項に記載の化合物および薬学的に許容されるキャリアを含む、医薬組成物。
- ループス、関節リウマチ、乾癬、移植片対宿主病、クローン病、炎症性腸疾患、多発性硬化症、循環器疾患、骨髄腫、リンパ腫、癌および細菌感染症からなる群から選択される障害を処置する方法であって、治療有効量の式IまたはIIの化合物をそれを必要としている患者に投与して前記障害の症状を軽減させることを含み、式Iは下記式で表され:
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり;
式IIは下記式で表され:
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、
方法。 - 前記化合物は式Iの化合物である、請求項29に記載の方法。
- 前記化合物は式IIの化合物である、請求項29に記載の方法。
- 前記化合物は表I〜Vに記載される化合物の1つである、請求項29に記載の方法。
- 前記障害はクローン病、炎症性腸疾患、多発性硬化症、移植片対宿主病、ループス、関節リウマチまたは乾癬である、請求項29〜41のいずれか1項に記載の方法。
- 前記障害は骨髄腫、リンパ腫、循環器疾患または癌である、請求項29〜41のいずれか1項に記載の方法。
- 前記障害は細菌感染症である、請求項29〜41のいずれか1項に記載の方法。
- F1F0−ATPアーゼを阻害する方法であって、F1F0−ATPアーゼを請求項1〜27のいずれか1項に記載の化合物に曝露することを含む、方法。
- 前記F1F0−ATPアーゼはミトコンドリアF1F0−ATPアーゼである、請求項45に記載の方法。
- F1F0−ATPアーゼ阻害剤を同定する方法であって:
a)以下を得ること、
i)ミトコンドリアF1F0−ATPアーゼを含むサンプル、
ii)式IまたはIIのグアニジン化合物を含む第1の組成物であって、式Iは下記式で表され:
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり;
式IIは下記式で表され:
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、化合物;
iii)候補F1F0−ATPアーゼ阻害剤を含む第2の組成物;
b)前記サンプルを前記第1の組成物および前記第2の組成物と接触させること;
c)前記グアニジン化合物および前記候補F1F0−ATPアーゼ阻害剤の前記ミトコンドリアF1F0−ATPアーゼ結合親和性を測定すること;
d)前記グアニジン化合物および前記候補F1F0−ATPアーゼ阻害剤の前記ミトコンドリアF1F0−ATPアーゼ結合親和性を比較すること;および、
e)前記候補F1F0−ATPアーゼ阻害剤の前記結合親和性および前記サンプルの細胞生存率を評価することにより前記候補F1F0−ATPアーゼ阻害剤をF1F0−ATPアーゼ阻害剤として同定すること、
を含む、方法。 - 前記ミトコンドリアF1F0−ATPアーゼ結合親和性を測定する前記ステップは前記ミトコンドリアF1F0−ATPアーゼのOSCPの結合を測定することを含む、請求項47に記載の方法。
- ミトコンドリアF1F0−ATPアーゼ阻害剤を同定する方法であって:
a)以下を得ること:
i)ミトコンドリアF1F0−ATPアーゼを含む第1および第2のサンプル、
ii)式IまたはIIのグアニジン化合物を含む第1の組成物であって、式Iは下記式で表され:
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり;
式IIは下記式で表され:
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、化合物;および、
iii)候補ミトコンドリアF1F0−ATPアーゼ阻害剤を含む第2の組成物;
b)前記第1のサンプルを前記第1の組成物と接触させること;
c)前記第2のサンプルを前記第2の組成物と接触させること;
d)前記第1および第2のサンプルの前記ミトコンドリアF1F0−ATPアーゼ活性を測定すること;
e)前記第1および第2のサンプルの前記ミトコンドリアF1F0−ATPアーゼ活性を比較すること;および、
f)ミトコンドリアF1F0−ATPアーゼ活性を評価することにより前記候補ミトコンドリアF1F0−ATPアーゼ阻害剤をミトコンドリアF1F0−ATPアーゼ阻害剤として同定すること、
を含む、方法。 - ミトコンドリアF1F0−ATPアーゼ活性を測定する前記ステップは前記グアニジン化合物および前記候補ミトコンドリアF1F0−ATPアーゼ阻害剤の前記OSCP結合親和性を測定することを含む、請求項49に記載の方法。
- ミトコンドリアF1F0−ATPアーゼ活性を測定する前記ステップは前記第1および第2のサンプル中のスーパーオキシドレベルを測定することを含む、請求項50に記載の方法。
- ミトコンドリアF1F0−ATPアーゼ阻害剤を同定する方法であって:
a)式IまたはIIで表される1種または複数種の化合物であって、式Iは下記式で表され:
R1は、
X1は−N(R2)−、Oまたは−C(R6)2−であり;
X2は−N(H)−、−N(アルキル)−、−N(ヒドロキシアルキル)−、O、Sまたは−C(R6)2−であり;
X3は−N(R2)−、−C(R6)2−または−C(R6)2C(R6)2−であり;
R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキル、−NO2または−CNを表し;
R6は出現するごとに独立に水素またはアルキルを表し;
R7は出現するごとに独立にハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
R8は出現するごとに独立に水素、ハロゲン、アルキル、ハロアルキルまたはアルコキシを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式Iで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり;
式IIは下記式で表され:
R1、R2およびR3は出現するごとに独立に水素または(C1〜C4)アルキルを表し;
R4は、
R5は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
R6は出現するごとに独立に(C4〜C6)アルキルまたはハロアルキルを表し;
R7は出現するごとに独立に水素、ハロゲン、アルキルまたはハロアルキルを表し;
nは0、1、2、3または4であり;
mは出現するごとに独立に1または2を表し;
式IIで表される化合物の立体中心の立体配置はR、Sまたはこれらの混合物であり、ただしR5がハロゲンである場合、R6はハロアルキルではない、化合物を得ること;
b)式Iの前記1種または複数種の化合物の化学構造を改変して候補ミトコンドリアF1F0−ATPアーゼ阻害剤のライブラリーを作成すること;および、
c)ミトコンドリアF1F0−ATPアーゼを含むサンプルに前記ライブラリーを曝露すること;および、
d)前記それぞれのサンプルの前記ミトコンドリアF1F0−ATPアーゼ活性を阻害するミトコンドリアF1F0−ATPアーゼ阻害剤として前記候補ミトコンドリアF1F0−ATPアーゼ阻害剤を同定すること、
を含む、方法。 - 前記ミトコンドリアF1F0−ATPアーゼ活性を阻害する前記ステップは前記それぞれのサンプル中にスーパーオキシドフリーラジカルを生成することを含む、請求項52に記載の方法。
- 前記ミトコンドリアF1F0−ATPアーゼ活性を阻害する前記ステップは前記それぞれのサンプル中に細胞死を起こすことを含む、請求項53に記載の方法。
- 前記化合物は式Iの化合物である、請求項45〜54のいずれか1項に記載の方法。
- 前記化合物は式IIの化合物である、請求項45〜54のいずれか1項に記載の方法。
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WO2010030891A3 (en) | 2010-06-03 |
WO2010030891A2 (en) | 2010-03-18 |
EP2352724B1 (en) | 2015-04-22 |
US8497307B2 (en) | 2013-07-30 |
US20110251200A1 (en) | 2011-10-13 |
JP5567573B2 (ja) | 2014-08-06 |
AU2009291632B2 (en) | 2013-04-04 |
EP2352724A4 (en) | 2012-05-30 |
AU2009291632A1 (en) | 2010-03-18 |
EP2352724A2 (en) | 2011-08-10 |
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