JP2014080440A - Cftr修飾因子としてのへテロアリール誘導体 - Google Patents
Cftr修飾因子としてのへテロアリール誘導体 Download PDFInfo
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- JP2014080440A JP2014080440A JP2014022276A JP2014022276A JP2014080440A JP 2014080440 A JP2014080440 A JP 2014080440A JP 2014022276 A JP2014022276 A JP 2014022276A JP 2014022276 A JP2014022276 A JP 2014022276A JP 2014080440 A JP2014080440 A JP 2014080440A
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- dioxol
- benzo
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- cyclopropanecarboxamide
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Abstract
【解決手段】本発明は、嚢胞性線維症膜コンダクタンス制御因子(「CFTR」)を含むATP結合カセット(「ABC」)トランスポーターまたはその断片の修飾因子、その組成物および方法に関する。本発明は、そうした修飾因子を用いてABCトランスポーター媒介疾患を治療する方法にも関する。本発明の化合物および薬学的に許容されるその組成物は、ABCトランスポーター活性、特にCFTR活性の修飾因子として有用であることをここに見出した。これらの化合物は一般式Iを有する化合物または薬学的に許容されるその塩である。
【選択図】なし
Description
Sci. USA 87巻:8447〜8451頁)。これまで、CF遺伝子において1000を超える疾患誘発性の変異が特定されている(http://www.genet.sickkids.on.ca/cftr/)。最もよく見られる変異は、CFTRアミノ酸配列の位置508でのフェニルアラニンの欠失であり、通常ΔF508−CFTRと称される。この変異は嚢胞性線維症の症例の約70%において発生し、重症疾患と関連している。
本発明は、例えば以下の項目を提供する。
(項目1)
式Iの化合物:
Ar1は
Ar1は、w個出現する−W−RWで任意選択で置換されており;
Wは独立に、結合または任意選択で置換された(C1〜C6)アルキリデン鎖であり、Wのうちの最大で2つのメチレン単位は独立に、−CO−、−O−、−S−、−SO2−または−NR’−で置き換えられており;
R’は独立に、H、アルキル、アリール、ヘテロアリール、アラルキル、シクロアルキルまたはヘテロシクロアルキルであり;
RWは独立に、H、ハロ、CN、NO2、NH2、CF3、OCF3、OH、アルコキシまたは任意選択で置換された脂肪族、脂環式、複素環式、アリールもしくはヘテロアリールであり、置換されている場合、RWは最大で2つのR2で置換されており;
R2は、ハロ、CN、NO2、CF3、OCF3、OR、−(C1〜C6)アルキリデン−OH、−(C1〜C6)アルキリデン−N(R)2、OC(O)R、OC(O)N(R)2、SR、S(O)R、SO2R、SO2N(R)2、SO3R、C(O)R、CO2R、C(O)N(R)2、N(R)2、NRC(O)R、NRCO2R、NRC(O)N(R)2、NRSO2R、B(OR)2またはNRSO2N(R)2であり;
Rは独立に、H、アルキル、シクロアルキル、複素環式、アリールまたはヘテロアリールであり;
RNはH、アルキル、アリール、ヘテロアリール、アラルキル、シクロアルキルまたはヘテロシクロアルキルであり;
Aは任意選択で置換された3〜7員単環であり;
Bは、脂環式、アリール、複素環式およびヘテロアリールからなる群から選択される5〜7員環と任意選択で縮合しており;
Jは、CH2、CF2、C(CH3)2、C(O)、
wは独立に端値を含む0〜5の整数であり;
但し、Ar1が
または薬学的に許容されるその塩。
(項目2)
Aが、
qは端値を含む0〜4の整数である)
からなる群から選択される、項目1に記載の化合物。
(項目3)
Aが、
(項目4)
Aが、
(項目5)
JがCH2である、項目1に記載の化合物。
(項目6)
JがCF2である、項目1に記載の化合物。
(項目7)
RNがH、アリールまたはヘテロアリールである、項目1に記載の化合物。
(項目8)
RNがHまたはヘテロアリールである、項目1に記載の化合物。
(項目9)
RNがヘテロアリールである、項目1に記載の化合物。
(項目10)
RNがHである、項目1に記載の化合物。
(項目11)
任意選択で置換されたAr1が、
(項目12)
任意選択で置換されたAr1が、
(項目13)
任意選択で置換されたAr1が、
(項目14)
任意選択で置換されたAr1が、
(項目15)
任意選択で置換されたAr1が、
(項目16)
任意選択で置換されたAr1が、
(項目17)
wが0である、項目1に記載の化合物。
(項目18)
wが1である、項目1に記載の化合物。
(項目19)
wが2である、項目1に記載の化合物。
(項目20)
Wが結合である、項目1に記載の化合物。
(項目21)
Wが任意選択で置換された(C1〜C6)アルキリデン鎖である、項目1に記載の化合物。
(項目22)
Wが−CH2−である、項目1に記載の化合物。
(項目23)
Wが−NH−である、項目1に記載の化合物。
(項目24)
Wが−O−である、項目1に記載の化合物。
(項目25)
Wが−SO2−である、項目1に記載の化合物。
(項目26)
RWがHである、項目1に記載の化合物。
(項目27)
RWがOHである、項目1に記載の化合物。
(項目28)
RWがアリールである、項目1に記載の化合物。
(項目29)
RWがフェニルである、項目1に記載の化合物。
(項目30)
RWがヘテロアリールである、項目1に記載の化合物。
(項目31)
RWがピリジルである、項目1に記載の化合物。
(項目32)
RWがアルコキシである、項目1に記載の化合物。
(項目33)
RWがメトキシである、項目1に記載の化合物。
(項目34)
RWがトリフルオロメトキシである、項目1に記載の化合物。
(項目35)
RWがシクロアルキルである、項目1に記載の化合物。
(項目36)
RWがシクロヘキシルである、項目1に記載の化合物。
(項目37)
RWがヘテロシクロアルキルである、項目1に記載の化合物。
(項目38)
RWが不飽和ヘテロシクロアルキルである、項目1に記載の化合物。
(項目39)
RWがピリドンである、項目1に記載の化合物。
(項目40)
RWが−(C1〜C6)アルキリデン−N(R)2である、項目1に記載の化合物。
(項目41)
RWが−(C1〜C6)アルキリデン−OHである、項目1に記載の化合物。
(項目42)
RWが−CH2OHである、項目1に記載の化合物。
(項目43)
Ar1が非環式−W−RWで置換されている、項目1に記載の化合物。
(項目44)
Ar1が、アリール環、ヘテロアリール環またはシクロアルキル環である−W−RWで置換されている、項目1に記載の化合物。
(項目45)
Ar1が次式、
Wは結合または直鎖状もしくは分岐状(C1〜C6)アルキリデンであり、メチレン基は−O−、−SO2−または−NR’−で置換されていてよく;
R’はHまたはアルキルであり;
Cはアリールまたはヘテロアリールであり;
R4は、ハロ、−(C1〜C6)アルキル、CN、NO2、CF3、OCF3、OR、−(C1〜C6)アルキリデン−OH、SO2N(R)2、NRSO2R、C(O)R、CO2R、C(O)N(R)2、N(R)2またはNRC(O)Rであり;
qは端値を含む0〜5の整数である)
を有する少なくとも1つの−W−RWで置換されている、項目1に記載の化合物。
(項目46)
Ar1が以下の:−OH、−CH3、−OMe、−CN、−CF3、
(項目47)
Ar1が以下の:
(項目48)
式Ia:
JはCH2またはCF2であり;
RNはH、アルキル、アリールまたはヘテロアリールであり;
Ar1は、
Ar1は、w個出現する−W−RWで任意選択で置換されており;
Wは独立に、結合または任意選択で置換された(C1〜C6)アルキリデン鎖であり、Wのうちの最大で2つのメチレン単位は独立に、−O−、−SO2−または−NR’−で置き換えられており;
R’は独立に、H、アルキルまたはアリールであり;
RWは独立に、H、ハロ、CN、CF3、OH、アルコキシまたは任意選択で置換された脂肪族、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリールであり、置換されている場合、RWは最大で2つのR2で置換されており;
R2はハロ、CF3、OR、−(C1〜C6)アルキリデン−OH、SO2N(R)2、CO2R、C(O)N(R)2、B(OR)2またはN(R)2であり;
Rは独立に、H、アルキル、シクロアルキル、複素環式、アリールまたはヘテロアリールであり;
wは端値を含む0〜5の整数であり;
但し、Ar1が
を有する、項目1に記載の化合物または薬学的に許容されるその塩。
(項目49)
JがCH2である、項目48に記載の化合物。
(項目50)
JがCF2である、項目48に記載の化合物。
(項目51)
RNがHまたはヘテロアリールである、項目48に記載の化合物。
(項目52)
RNがヘテロアリールである、項目48に記載の化合物。
(項目53)
RNがHである、項目48に記載の化合物。
(項目54)
Ar1が以下の;
(項目55)
Ar1が非環式−W−RWで置換されている、項目48に記載の化合物。
(項目56)
Ar1がアリール環、ヘテロアリール環またはシクロアルキル環である−W−RWで置換されている、項目48に記載の化合物。
(項目57)
Ar1が不飽和ヘテロシクロアルキルである−W−RWで置換されている、項目48に記載の化合物。
(項目58)
Ar1がピリドンである−W−RWで置換されている、項目48に記載の化合物。
(項目59)
Ar1が以下の:−OH、−CH3、−OMe、−CN、−CF3、
(項目60)
Ar1が以下の:
(項目61)
Ar1が以下の:
(項目62)
式Ib:
を有する、項目1に記載の化合物または薬学的に許容されるその塩。
(項目63)
式Ic:
を有する、項目1に記載の化合物または薬学的に許容されるその塩。
(項目64)
表1から選択される化合物。
(項目65)
(i)項目1に記載の化合物;および
(ii)薬学的に許容される担体
を含む医薬組成物。
(項目66)
粘液溶解薬、気管支拡張薬、抗生物質、抗感染症剤、抗炎症剤、CFTR修正因子および栄養剤からなる群から選択される追加の薬剤をさらに含む、項目65に記載の組成物。
(項目67)
細胞の膜中のABCトランスポーターを調節する方法であって、該細胞を項目1に記載の化合物と接触させるステップを含む方法。
(項目68)
前記ABCトランスポーターがCFTRである、項目67に記載の方法。
(項目69)
ABCトランスポーター活性に関係する患者の状態、疾患または障害を治療する方法であって、前記患者に項目1に記載の化合物を投与するステップを含む方法。
(項目70)
前記ABCトランスポーターがCFTRである、項目69に記載の方法。
(項目71)
前記状態、疾患または障害が、嚢胞性線維症、遺伝性肺気腫、遺伝性ヘモクロマトーシス、凝固−線維素溶解欠乏症、例えばタンパク質C欠乏症、1型遺伝性血管浮腫、脂質プロセッシング欠乏症、例えば家族性高コレステロール血症、1型乳糜血症、無βリポタンパク血症、リソソーム蓄積症、例えばI−細胞疾患/偽ハーラー症候群、ムコ多糖症、サンドホフ/テイサックス病、クリグラーナジャー病II型、多腺性内分泌障害/高インスリン血症、真性糖尿病、ラロン型小人症、ミレオペルオキシダーゼ欠乏症、原発性甲状腺機能低下症、メラノーマ、グリカノシスCDG1型、遺伝性肺気腫、先天性甲状腺機能亢進症、骨形成不全症、遺伝性低フィブリノゲン血症、ACT欠乏症、尿崩症(di)、神経下垂体性di、腎性DI、シャルコーマリートゥース症候群、ペリツェウスメルツバッハー病、神経変性疾患、例えばアルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、進行性核上麻痺、ピック病、いくつかのポリグルタミン神経疾患、例えばハンチントン病、脊髄小脳失調I型I、脊髄性および延髄性筋萎縮、歯状核赤核淡蒼球ルイ体および筋強直性ジストロフィー、ならびに海綿状脳疾患、例えば遺伝性クロイツフェルトヤコブ病、ファブリー病、ストロイスラーシャインカー症候群、COPD、ドライアイ疾患およびシェーグレン病から選択される、項目69に記載の方法。
(項目72)
インビトロまたはインビボで、生物学的試料中のABCトランスポーターまたはその断片の活性を測定するのに使用するキットであって:
(i)項目1に記載の化合物を含む第1の組成物;および
(ii)a)前記組成物を生物学的試料と接触させ;
b)該ABCトランスポーターまたはその断片の活性を測定する
ための取扱説明書
を含むキット。
本発明は、式Iの化合物:
式中、Ar1は:
Ar1は、w個出現する−W−RWで任意選択で置換されており;
Wは独立に、結合または任意選択で置換された(C1〜C6)アルキリデン鎖であり、Wのうちの最大で2つのメチレン単位は独立に、−CO−、−O−、−S−、−SO2−または−NR’−で置き換えられており;
R’は独立に、H、アルキル、アリール、ヘテロアリール、アラルキル、シクロアルキルまたはヘテロシクロアルキルであり;
RWは独立に、H、ハロ、CN、NO2、NH2、CF3、OCF3、OH、アルコキシ、または任意選択で置換された脂肪族、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリールであり、置換されている場合、RWは最大で2つのR2で置換されており;
R2は、ハロ、CN、NO2、CF3、OCF3、OR、−(C1〜C6)アルキリデン−OH、−(C1〜C6)アルキリデン−N(R)2、OC(O)R、OC(O)N(R)2、SR、S(O)R、SO2R、SO2N(R)2、SO3R、C(O)R、CO2R、C(O)N(R)2、N(R)2、NRC(O)R、NRCO2R、NRC(O)N(R)2、NRSO2R、B(OR)2またはNRSO2N(R)2であり;
Rは独立に、H、アルキル、シクロアルキル、複素環式、アリール、またはヘテロアリールであり;
RNはH、アルキル、アリール、ヘテロアリール、アラルキル、シクロアルキルまたはヘテロシクロアルキルであり;
Aは任意選択で置換された3〜7員単環であり;
Bは、脂環式、アリール、複素環式およびヘテロアリールからなる群から選択される5〜7員環と任意選択で縮合しており;
Jは、CH2、CF2、C(CH3)2、C(O)、
wは端値を含む0〜4の整数であり;
但し、Ar1が
本発明の化合物には、上記に概略説明し、かつ本明細書で開示する部類、下位部類および種によってさらに例示される化合物が含まれる。本明細書で用いるように、別段の指定のない限り以下の定義が適用されるものとする。
一実施形態では、本発明は式Iの化合物:
式中、
Ar1は
Ar1は、w個出現する−W−RWで任意選択で置換されており;
Wは独立に、結合または任意選択で置換された(C1〜C6)アルキリデン鎖であり、Wのうちの最大で2つのメチレン単位は独立に、−CO−、−O−、−S−、−SO2−または−NR’−で置き換えられており;
R’は独立に、H、アルキル、アリール、ヘテロアリール、アラルキル、シクロアルキルまたはヘテロシクロアルキルであり;
RWは独立に、H、ハロ、CN、NO2、NH2、CF3、OCF3、OH、アルコキシ、または任意選択で置換された脂肪族、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリールであり、置換されている場合、RWは最大で2つのR2で置換されており;
R2は、ハロ、CN、NO2、CF3、OCF3、OR、−(C1〜C6)アルキリデン−OH、−(C1〜C6)アルキリデン−N(R)2、OC(O)R、OC(O)N(R)2、SR、S(O)R、SO2R、SO2N(R)2、SO3R、C(O)R、CO2R、C(O)N(R)2、N(R)2、NRC(O)R、NRCO2R、NRC(O)N(R)2、NRSO2R、B(OH)2またはNRSO2N(R)2であり;
Rは独立に、H、アルキル、シクロアルキル、複素環式、アリールまたはヘテロアリールであり;
RNはH、アルキル、アリール、ヘテロアリール、アラルキル、シクロアルキルまたはヘテロシクロアルキルであり;
Aは任意選択で置換された3〜7員単環であり;
Bは、脂環式、アリール、複素環式およびヘテロアリールからなる群から選択される5〜7員環と任意選択で縮合しており;
Jは、CH2、CF2、C(CH3)2、C(O)、
wは端値を含む0〜4の整数であり;
但し、Ar1が
R3がアルキル、アルカリール、アリールまたはヘテロアリールであり;qがそれを含む0〜4の整数である、式Iおよび付随定義の化合物に関する。他の実施形態では、Aは
式中、
Wは直鎖状または分岐状(C1〜C6)アルキリデンであり、メチレン基は−O−、−SO2−または−NR’−で置き換えられていてよく;
R’はHまたはアルキルであり;
Cはアリールまたはヘテロアリールであり;
R4は、ハロ、−(C1〜C6)アルキル、CN、NO2、CF3、OCF3、OR、−(C1〜C6)アルキリデン−OH、SO2N(R)2、NRSO2R、C(O)R、CO2R、C(O)N(R)2、N(R)2、またはNRC(O)Rであり;
qは端値を含む0〜5の整数である。
式中:
JはCH2またはCF2であり;
RNはH、アルキル、アリールまたはヘテロアリールであり;
Ar1は;
Ar1はw個出現する−W−RWで任意選択で置換されており;
Wは独立に、結合または任意選択で置換された(C1〜C6)アルキリデン鎖であり、Wのうちの最大で2つのメチレン単位は独立に、−O−、−SO2−、またはNR’−で置き換えられており;
R’は独立に、H、アルキルまたはアリールであり;
RWは独立に、H、ハロ、CN、CF3、OH、アルコキシまたは任意選択で置換された脂肪族、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリールであり、置換されている場合、RWは最大で2つのR2で置換されており;
R2は、ハロ、CF3、OR、−(C1〜C6)アルキリデン−OH、SO2N(R)2、CO2R、C(O)N(R)2、B(OH)2またはN(R)2であり
Rは独立に、H、アルキル、シクロアルキル、複素環式、アリールまたはヘテロアリールであり;
wは端値を含む0〜4の整数であり;
但し、Ar1が
式Iの化合物は当業界で周知の方法で調製することができる。式Iの化合物を調製するための方法の例を以下に示す。以下のスキームIは式Iの化合物の合成法の例を示すものである。
本発明の化合物は、公知の方法によりスキームI〜IIIに示すようにして調製することができる。
薬学的に許容される組成物
上記で論じたように、本発明は、ABCトランスポーターの調節因子として有用であり、したがって嚢胞性線維症、遺伝性肺気腫、遺伝性ヘモクロマトーシス、凝集線維素溶解欠乏症、例えばタンパク質C欠乏症、1型遺伝性血管性浮腫、脂質プロセッシング欠乏症、例えば家族性高コレステロール血症、1型乳糜血症、無βリポタンパク血症、リソソーム蓄積症、例えばアイセル病/偽ハーラー病、ムコ多糖症、サンドホフ病/テイサックス病、クリグラーナジャー病II型、多腺性内分泌障害/高インスリン血、真性糖尿病、ラロン型小人症、ミエロペルオキシダーゼ欠乏症、原発性甲状腺機能低下症、黒色腫、グリカン糖鎖異常CDG1型、遺伝性肺気腫、先天性甲状腺機能亢進症、骨形成不全症、遺伝性低フィブリノゲン血症、ACT欠乏症、尿崩症(DI)、神経下垂体性DI、腎性DI、シャルコーマリートゥース症候群、ペリツェウスメルツバッハー病、神経変性疾患、例えばアルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、進行性核上麻痺、ピック病、いくつかのポリグルタミン神経障害、例えばハンチントン病、脊髄小脳失調I型、脊髄性および延髄性筋萎縮、歯状核赤核淡蒼球ルイ体および筋強直性ジストロフィー症、ならびに海綿状脳症、例えば遺伝性クロイツフェルトヤコブ病(プリオンタンパク質プロセッシング異常に起因)、ファブリー病、シュトロイスラー−シャインカー症候群、COPD、ドライアイ疾患およびシェーグレン病などの疾患、障害または状態を治療するのに有用な化合物を提供する。
さらに他の態様では、本発明は、ABCトランスポーター活性に関係する状態、疾患または障害を治療する方法を提供する。特定の実施形態では、本発明は、ABCトランスポーター活性の欠損に関係する状態、疾患または障害を治療する方法であって、式(I)の化合物を含む組成物をそれを必要とする対象、好ましくは哺乳動物に投与することを含む方法を提供する。
handler)および蛍光検出器である、VIPR(商標)IIを用いてモニターすることができる。
31.7ミリモル)、1−ブロモ−2−クロロ−エタン(9.00mL 109ミリモル)および塩化ベンジルトリエチルアンモニウム(0.181g、0.795ミリモル)の混合物を70℃で加熱し、次いで50%(重量/重量)の水酸化ナトリウム水溶液(26mL)を混合物に徐々に加えた。反応物を70℃で24時間攪拌し、次いで130℃で48時間加熱した。暗褐色の反応混合物を水(400mL)で希釈し、等体積の酢酸エチルで1回、等体積のジクロロメタンで1回抽出した。塩基性の水溶液を濃塩酸で1未満のpHまで酸性化し、沈殿物をろ過し、1M塩酸で洗浄した。固形物をジクロロメタン(400mL)に溶解させ、等体積の1M塩酸で2回、塩化ナトリウムの飽和水溶液で1回抽出した。有機溶液を硫酸ナトリウムで脱水し、乾燥するまで蒸発させて白色からやや灰白色の固体(5.23g、80%)を得た。ESI−MS m/z 計算値206.1、実測値207.1(M+1)+。保持時間2.37分。
1H NMR (400 MHz, DMSO−d6) δ 1.07−1.11 (m, 2H), 1.38−1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).
1−(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−シクロプロパンカルボン酸の調製
アセトニトリル(30mL)およびトリエチルアミン(10mL)を含むメタノール(20mL)中の5−ブロモ−2,2−ジフルオロ−ベンゾ[1,3]ジオキソール(11.8g、50.0ミリモル)およびテトラキス(トリフェニルホスフィン)パラジウム(0)[Pd(PPh3)4、5.78g、5.00ミリモル]の溶液を、一酸化炭素雰囲気(55PSI)下、75℃(油浴温度)で15時間攪拌した。冷却した反応混合物をろ過し、蒸発させて乾燥した。残留物をシリカゲルカラムクロマトグラフィーで精製して粗2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−カルボン酸メチルエステル(11.5g)を得た。これを、次のステップで直接使用した。
20mLの無水テトラヒドロフラン(THF)に溶解した粗2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−カルボン酸メチルエステル(11.5g)を、無水THF(100mL)中の水素化アルミニウムリチウム(4.10g、106ミリモル)の懸濁液に0℃で徐々に加えた。次いで混合物を室温に加温した。室温で1時間攪拌した後、反応混合物を0℃に冷却し、水(4.1g)で処理し、続いて水酸化ナトリウム(10%水溶液、4.1mL)で処理した。得られたスラリーをろ過し、THFで洗浄した。一緒にしたろ液を蒸発させて乾燥し、残留物をシリカゲルカラムクロマトグラフィーで精製して(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−メタノール(7.2g、38ミリモル、2つのステップ合わせて76%)を無色油状物として得た。
塩化チオニル(45g、38ミリモル)を、ジクロロメタン(200mL)中の(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−メタノール(7.2g、38ミリモル)の溶液に0℃で徐々に加えた。得られた混合物を室温で終夜攪拌し、蒸発させて乾燥した。残留物を飽和炭酸水素ナトリウムの水溶液(100mL)とジクロロメタン(100mL)に分配させた。分離した水層をジクロロメタン(150mL)で抽出し、有機層を硫酸ナトリウムで脱水し、ろ過し、蒸発させて乾燥して粗5−クロロメチル−2,2−ジフルオロ−ベンゾ[1,3]ジオキソール(4.4g)を得た。これを、さらに精製することなく次のステップで直接使用した。
ジメチルスルホキシド(50mL)中の粗5−クロロメチル−2,2−ジフルオロ−ベンゾ[1,3]ジオキソール(4.4g)とシアン化ナトリウム(1.36g、27.8ミリモル)の混合物を室温で終夜攪拌した。反応混合物を氷に注加し、酢酸エチル(300mL)で抽出した。有機層を硫酸ナトリウムで脱水し、蒸発させて乾燥して粗(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−アセトニトリル(3.3g)を得た。これを、次のステップで直接使用した。
水酸化ナトリウム(50%水溶液、10mL)を、粗(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−アセトニトリル、ベンジルトリエチルアンモニウムクロリド(3.00g、15.3ミリモル)および1−ブロモ−2−クロロエタン(4.9g、38ミリモル)の混合物に70℃で徐々に加えた。混合物を70℃で終夜攪拌し、続いて反応混合物を水(30mL)で希釈し、酢酸エチルで抽出した。一緒にした有機層を硫酸ナトリウムで脱水し、蒸発させて乾燥して粗1−(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−シクロプロパンカルボニトリルを得た。これを、次のステップで直接使用した。
1−(2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−5−イル)−シクロプロパンカルボニトリル(最後のステップからの粗製物)を10%水酸化ナトリウム水溶液(50mL)中で2.5時間還流させた。冷却した反応混合物をエーテル(100mL)で洗浄し、水相を2M塩酸でpH2に酸性化させた。沈殿した固形物をろ過して1−(2,2−ジフルオロベンゾ[1,3]ジオキソール−5−イル)−シクロプロパンカルボン酸を白色固体(0.15g、4つのステップ合わせて1.6%)として得た。ESI−MS
m/z 計算値242.04、実測値;241.58(M+1)+:
1H NMR (CDCl3) δ 7.14−7.04 (m, 2H), 6.98−6.96 (m, 1H), 1.74−1.64 (m, 2H), 1.26−1.08 (m, 2H).
1−(ベンゾ[d][1,3]ジオキソール−5−イル)−N−(5−ブロモ−6−メチルピリジン−3−イル)シクロプロパンカルボキサミドの調製
1H NMR (400 MHz, CD3CN) δ 8.38 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.80−7.60 (m, 1H), 7.08−6.95 (s, 2H), 6.89
(dd, J = 1.2, 7.3 Hz, 1H), 6.01 (s, 2H), 2.54 (s, 3H), 1.59−1.50 (m, 2H), 1.19−1.09 (m, 2H).
1−(ベンゾ[d][1,3]ジオキソール−5−イル)−N−(6−メチル−5−フェニルピリジン−3−イル)シクロプロパンカルボキサミドの調製
1−(ベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボン酸(9.50g、46.00ミリモル)に、塩化チオニル(10.00mL、138.00ミリモル)およびDMF(4滴)を加え、混合物(mistrure)を攪拌し、60℃で30分間加熱した。過剰の塩化チオニルを減圧下で蒸発させた。酸クロリドの一部(23.20ミリモル)をピリジン(15mL)に溶解し、ピリジン(10mL)中の6−ブロモピリジン−3−アミン(23.20ミリモル)に徐々に加えた。反応混合物を110℃で1時間30分攪拌した。ピリジンを減圧下で蒸発させた。得られた混合物をジクロロメタン(200mL)に溶解し、1N NaOH(4×50mL)で洗浄した。有機層を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製して1−(ベンゾ[d][1,3]ジオキソール−5−イル)−N−(6−ブロモピリジン−3−イル)シクロプロパンカルボキサミド(4g、48%)を得た。
THF中の(2−メトキシベンジル)亜鉛(II)クロリド(4.44mL、0.5M、2.20ミリモル)の溶液および(DPPF)2PdCl2・CH2Cl2(45mg、0.056ミリモル)を室温で20分間攪拌した。これにTHF(4mL)中の1−(ベンゾ[d][1,3]ジオキソール−5−イル)−N−(6−ブロモピリジン−3−イル)シクロプロパンカルボキサミド(200mg、0.56ミリモル)のスラリーを加え、反応混合物をマイクロ波反応器中、150℃で10分間加熱した。得られた物質を室温に冷却した。Na2EDTAおよびNH4Cl飽和水溶液を反応物に加え、混合物を室温で30分間攪拌した。生成物を、ジクロロメタンで抽出した。有機層を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製して1−(ベンゾ[d][1,3]ジオキソール−5−イル)−N−(6−(2−メトキシベンジル)ピリジン−3−イル)シクロプロパンカルボキサミド(152mg、68%)を得た。
塩化チオニル(1.6mL、21.8ミリモル)中の1−(ベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボン酸(1.5g、7.3ミリモル)に、N,N−ジメチルホルムアミド(100μL)を加えた。反応混合物を室温で30分間攪拌し、続いてこれを乾燥するまで蒸発させて所望の酸クロリドを得た。酸クロリドをピリジン(10mL)中の2−クロロピリジン−4−アミン(0.94g、7.3ミリモル)の溶液に加えた。反応物を100℃で12時間加熱した。反応物をジクロロメタン(30mL)で希釈し、1N NaOH(3×20mL)で洗浄した。有機物をNa2SO4で脱水し、乾燥するまで蒸発させた。粗製物質をシリカゲルクロマトグラフィーで(ヘキサン中の0〜50%酢酸エチルで溶出させて)精製して所望生成物を得た。ESI−MS m/z 計算値316.06、実測値317.1(M+1)+。保持時間2.97分。
THF(0.8mL、0.4ミリモル)中のベンジル亜鉛(II)ブロミドの0.5M溶液に、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(8mg、0.01ミリモル)を加え、反応物を窒素雰囲気下で20分間攪拌した。1−(ベンゾ[d][1,3]ジオキソール−5−イル)−N−(2−クロロピリジン−4−イル)シクロプロパンカルボキサミド(32mg、0.10ミリモル)を加え、マイクロ波反応器中で反応物に150℃で10分間照射した。反応物を飽和塩化アンモニウム溶液(2mL)および飽和エチレンジアミン4酢酸ジナトリウム塩溶液(2mL)でクエンチした。混合物を30分間攪拌し、次いでジクロロメタン(3×4mL)で抽出した。有機物をNa2SO4で脱水し、蒸発させた。粗生成物をDMSO(1mL)に溶解させ、0.05%トリフルオロ酢酸を含有する0〜99%の勾配のアセトニトリル水溶液を用いて逆相分取液体クロマトグラフィーで精製して純粋な生成物(18mg、0.048ミリモル、48%)を得た。ESI−MS m/z 計算値372.1、実測値373.3(M+1)+;保持時間2.44分。
新たに調製したナトリウムメトキシド(10.8g、200ミリモル)を、DMF(20mL)中のプロピオン酸エチル(15.3g、150ミリモル)の溶液に室温で懸濁させた。ギ酸メチル(6.0g、100ミリモル)を1時間かけて添加した。30分間攪拌した後、MeOH(35mL)中の塩酸グアニジン(9.6gg、100ミリモル)の溶液を急速に加え、反応混合物を12時間還流させた。30℃に冷却し、濃塩酸でpHを6.0に調節した後、スラリーを5℃で30分間保持した。固形物を集め、メタノールで洗浄し、水から結晶化させ、真空下で乾燥して5−メチルイソシトシン(7.3g、58.4%収率)を得た。
1H NMR (300 MHz, DMSO): δ 10.83 (br s, 2
H), 7.38 (s, 1 H), 6.26 (br s, 2 H), 1.72 (s, 3 H).
ステップb:4−クロロ−2−アミノ−5−メチルピリミジン
5−メチルイソシトシン(3g、24.0ミリモル)とPOCl3(20mL)の混合物を45分間還流させた。減圧下で過剰のPOCl3を除去し、残留物を氷に注加した。得られた混合物を10℃で、アンモニアで塩基性にした。沈殿物をろ過し、エタノールから結晶化させて4−クロロ−2−アミノ−5−メチルピリミジン(1g 29.0%収率)を得た。
1H NMR (400 MHz, DMSO): δ 8.11 (s, 1 H),
6.81 (br s, 2 H), 2.04 (s, 3 H).
ステップc:tert−ブチル3−(2−アミノ−5−メチルピリミジン−4−イル)ベンゾエート
4−クロロ−5−メチルピリミジン−2−アミン(150mg、1.04ミリモル)、テトラキストリフェニルホスフィンパラジウム(0)(60mg、0.052ミリモル)および3−(tert−ブトキシカルボニル)フェニルボロン酸(347mg、1.56ミリモル)に、1,2−DME(3mL)およびNa2CO3(1.04mL、2M、2.08ミリモル)を加え、マイクロ波反応器中、120℃で30分間加熱した。EtOAcを用いて反応混合物をろ過し、ろ液を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製してtert−ブチル3−(2−アミノ−5−メチルピリミジン−4−イル)ベンゾエート(148mg、50%)を得た。ESI−MS m/z 計算値285.1、実測値286.5(M+1)+。保持時間1.33分。
1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボニルクロリド(91mg、0.35ミリモル)およびtert−ブチル3−(2−アミノ−5−メチルピリミジン−4−イル)ベンゾエート(50mg、0.175ミリモル)に、ピリジン(2mL)を加えた。反応物を90℃で24時間加熱した。ピリジンを減圧下で蒸発させた。得られた混合物を酢酸エチルに溶解し、ろ過した。ろ液をNaHCO3飽和水溶液(×3)で洗浄した。有機層を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製してtert−ブチル3−(2−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−5−メチルピリミジン−4−イル)ベンゾエートを得た。ESI−MS m/z 計算値509.18、実測値510.5(M+1)+。保持時間2.22分。
tert−ブチル3−(2−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−5−メチルピリミジン−4−イル)ベンゾエート(48mg、0.094ミリモル)に、ジクロロメタン(dicloromethane)(1mL)およびTFA(726μL)を加え、室温で4時間攪拌した。減圧下でジクロロメタンおよびTFAを蒸発させた。粗生成物をDMSO(1mL)に溶解し、ろ過し、逆相分取HPLCで精製して3−(2−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−5−メチルピリミジン−4−イル)安息香酸を得た。ESI−MS m/z 計算値453.11、実測値454.3(M+1)+。保持時間1.63分。
4−クロロ−5−メチルピリミジン−2−アミン(150mg、1.04ミリモル)、テトラキストリフェニルホスフィンパラジウム(0)(60mg、0.052ミリモル)および4−(tert−ブトキシカルボニル)フェニルボロン酸(347mg、1.56ミリモル)に、1,2−DME(3mL)およびNa2CO3(1.04mL、2M、2.08ミリモル)を加え、マイクロ波反応器中、120℃で30分間加熱した。EtOAcを用いて反応混合物をろ過し、ろ液を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製してtert−ブチル4−(2−アミノ−5−メチルピリミジン−4−イル)ベンゾエート(149mg、50%)を得た。ESI−MS m/z 計算値285.1、実測値286.3(M+1)+。保持時間1.36分。
1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボニルクロリド(91mg、0.35ミリモル)およびtert−ブチル4−(2−アミノ−5−メチルピリミジン−4−イル)ベンゾエート(50mg、0.175ミリモル)に、ピリジン(2mL)を加えた。反応物を90℃で24時間加熱した。ピリジンを減圧下で蒸発させた。得られた混合物をEtOAcに溶解し、ろ過した。ろ液をNaHCO3飽和水溶液(×3)で洗浄した。有機層を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製してtert−ブチル4−(2−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−5−メチルピリミジン−4−イル)ベンゾエートを得た。ESI−MS m/z 計算値509.2、実測値510.5(M+1)+。保持時間2.18分。
tert−ブチル4−(2−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−5−メチルピリミジン−4−イル)ベンゾエート(68mg、0.13ミリモル)に、DCM(1.42mL)およびTFA(1.00mL)を加え、室温で1時間攪拌した。DCMおよびTFAを減圧下で蒸発させた。粗生成物をDMSO(1mL)に溶解し、ろ過し、逆相分取HPLCで精製して4−(2−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−5−メチルピリミジン−4−イル)安息香酸を得た。ESI−MS m/z 計算値453.1、実測値454.3(M+1)+。保持時間1.62分。
4−クロロ−5−メチルピリミジン−2−アミン(250mg、1.74ミリモル)、テトラキストリフェニルホスフィンパラジウム(0)(100mg、0.087ミリモル)および6−メトキシピリジン−3−イルボロン酸(398mg、2.60ミリモル)に、1,2−DME(6mL)およびNa2CO3(1.74mL、2M、3.47ミリモル)を加え、マイクロ波反応器中、120℃で30分間加熱した。アセトニトリルを用いて反応混合物をろ過し、ろ液を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製して4−(6−メトキシピリジン−3−イル)−5−メチルピリミジン−2−アミン(160mg、43%)を得た。ESI−MS m/z 計算値216.10、実測値217.5(M+1)+。保持時間0.52分。
1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボニルクロリド(369mg、1.42ミリモル)および4−(6−メトキシピリジン−3−イル)−5−メチルピリミジン−2−アミン(153mg、0.71ミリモル)に、ピリジン(4mL)を加えた。反応物を90℃で3.5時間加熱した。ピリジンを減圧下で蒸発させた。得られた混合物を酢酸エチルに溶解し、ろ過した。ろ液をNaHCO3飽和水溶液(×3)で洗浄した。有機層を無水Na2SO4で脱水し、減圧下で蒸発させた。粗生成物を、シリカゲルを用いてカラムクロマトグラフィーで精製して1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)−N−(4−(6−メトキシピリジン−3−イル)−5−メチルピリミジン−2−イル)シクロプロパンカルボキサミドを得た。ESI−MS m/z 計算値440.13、実測値441.5(M+1)+。保持時間1.72分。
化合物のΔF508−CFTR調節特性をアッセイするための膜電位の光学的方法
このアッセイは、蛍光プレートリーダー(例えば、FLIPR III、Molecular Devices、Inc.)を用いて、膜電位の変化を、NIH 3T3細胞における機能的ΔF508−CFTRの増加の読取りとして測定する蛍光電位感受性染料を使用する。その応答の推進力は、細胞を予め化合物で処理し、次いで電位感受性染料をロードした後の単一の液体添加ステップによる、チャネル活性化と合わせたクロリドイオン勾配の形成である。
ΔF508−CFTRに伴う輸送障害を修正する小分子を同定するために、単一添加HTSアッセイフォーマットを開発した。細胞を含むアッセイプレートを、組織培養インキュベーター中、37℃、5%CO2、90%湿度で約2〜4時間インキュベートする。次いで、アッセイプレートの底部に付着させて、細胞が化合物に曝露されるようにする。
ΔF508−CFTRの増強因子を特定するために、二重添加HTSアッセイフォーマットを開発した。このHTSアッセイは、温度補正されたΔF508 CFTR NIH
3T3細胞における、ΔF508 CFTRのゲーティング(コンダクタンス)の増大の測定として、蛍光電位感受性染料を用いてFLIPR IIIに対する膜電位の変化を測定する。その応答の推進力は、細胞を予め増強因子化合物(またはDMSO媒体対照)で処理し、次いで再分配染料をロードした後にFLIPR IIIなどの蛍光プレートリーダーを用いた単一液体添加ステップでのホルスコリンによるチャネル活性化と合わせたCl−イオン勾配である。
浴溶液#1:(mMで) NaCl 160、KCl 4.5、CaCl2 2、MgCl2 1、HEPES 10、NaOHでpH7.4に。
クロリドフリー浴溶液: 浴溶液#1中のクロリド塩をグルコン酸塩で置き換える。
ΔF508−CFTRを安定的に発現するNIH3T3マウス線維芽細胞を、膜電位の光学的測定のために使用する。細胞を、175cm2培養フラスコの中で、2mMグルタミン、10%ウシ胎仔血清、1X NEAA、β−ME、1X pen/strep(ペニシリン/ストレプトマイシン)および25mM HEPESを含むダルベッコ変法イーグル培地中、5%CO2、90%の湿度の雰囲気下、37℃で保持した。すべての光学的アッセイのために、細胞を、384ウェルのマトリゲルコーティングしたプレートに約20,000/ウェルで播種し、37℃で2時間培養し、続いて、増強因子アッセイのために27℃で24時間培養した。修正アッセイのため、化合物を含めるまたは含めないで、細胞を27℃または37℃で16〜24時間培養した。
1.Ussingチャンバーアッセイ
ΔF508−CFTRを発現する分極した気道上皮細胞でUssingチャンバー実験を実施して、光学的アッセイで特定されたΔF508−CFTR修飾因子をさらに特性評価した。非CFおよびCF気道上皮を気管支組織から単離し、既述されているようにして培養し(Galietta,L.J.V.、Lantero,S.、Gazzolo,A.、Sacco,O.、Romano,L.、Rossi,G.A.、& Zegarra−Moran、O.(1998年)In Vitro Cell.Dev.Biol.、34巻、478〜481頁)、NIH3T3馴化培地をプレコートしたCostar(登録商標)Snapwell(商標)フィルター上に蒔いた。4日後、頂端部の培地を取り除き、使用する前に、細胞を気液界面で>14日間成長させた。これによって、繊毛を有する(気道上皮の特徴である)完全に分化した柱状細胞の単層が得られた。非CF HBEを、公知の肺病をまったく有していない非喫煙者から単離した。CF−HBEを、ΔF508−CFTRにホモ接合である患者から単離した。
典型的な手順では、側底側膜から頂端側膜へのCl−濃度勾配を用いた。この勾配を設定するために、標準的リンガー液(normal ringer)を側底膜上で用いたが、上皮を横断した大きなCl−濃度勾配を得るために、頂端側NaClを、等モルのグルコン酸ナトリウム(NaOHで滴定してpH7.4)で置き換えた。すべての実験はインタクトな単分子層を用いて実施した。ΔF508−CFTR、ホルスコリン(10μM)、PDE阻害剤、IBMX(100μM)およびCFTR増強因子を完全に活性化させるために、ゲニステイン(50μM)を頂端側に加えた。
典型的な手順では、側底側膜から頂端側膜へのCl−濃度勾配を用いた。この勾配を設定するために、標準的リンガー液を側底膜上で用いたが、上皮を横断した大きなCl−濃度勾配を得るために、頂端側NaClを、等モルのグルコン酸ナトリウム(NaOHで滴定してpH7.4)で置き換えた。ホルスコリン(10μM)およびすべての試験化合物を細胞培養インサートの頂端側に加えた。推定ΔF508−CFTR増強因子の効力を、公知の増強因子、ゲニステインのそれと比較した。
ΔF508−NIH3T3細胞における合計Cl−電流を、既述されているようにして穿孔パッチ記録構成を用いてモニターした(Rae,J.、Cooper,K.、Gates,P.、& Watsky,M.(1991年)J.Neurosci.Methods 37巻、15〜26頁)。Axopatch 200Bパッチクランプ増幅器(Axon Instruments Inc.、Foster City、CA)を用いて、電圧クランプを22℃で記録した。ピペット液は(mMで)、150 N−メチル−D−グルカミン(NMDG)−Cl、2 MgCl2、2 CaCl2、10 EGTA、10 HEPESおよび240μg/ml アンフォテリシン−B(pHをHClで7.35に調節)を含んだ。細胞外培地は(mMで)、150 NMDG−Cl、2 MgCl2、2 CaCl2、10 HEPES(pHをHClで7.35に調節)を含んだ。パルス発生、データの収集および分析を、Digidata1320A/Dインターフェースと合わせてClampex8(Axon Instruments Inc.)を備えたPCを用いて実施した。ΔF508−CFTRを活性化させるために、10μMホルスコリンおよび20μMゲニステインを浴に加え、電流−電圧関係を30秒ごとにモニターした。
原形質膜中の機能的ΔF508−CFTRの密度を増大させることについての修正化合物の活性を判定するために、発明者らは、修正化合物を用いて24時間処置した後、上記の穿孔パッチ記録法を用いて電流密度を測定した。ΔF508−CFTRを十分に活性化するために、10μMホルスコリンおよび20μMゲニステインを細胞に加えた。発明者らの記録条件下で、27℃で24時間インキュベーションした後の電流密度は、37℃で24時間インキュベーションした後の電流密度より大きかった。これらの結果は、原形質膜におけるΔF508−CFTRの密度に対する低温インキュベーションの公知の効果と一致する。CFTR電流密度に対する修正化合物の効果を判定するために、細胞を10μMの試験化合物で、37℃で24時間インキュベートし、電流密度を27℃および37℃制御(活性率%)と比較した。記録する前に、細胞を細胞外の記録媒体で3回洗浄して任意の残留する試験化合物を除去した。10μMの修正化合物でのプレインキュベーションは、37℃制御と比較して、cAMP依存性電流およびゲニステイン依存性電流を大幅に増大させた。
穿孔パッチ記録法を用いて、ΔF508−CFTR増強因子が、ΔF508−CFTRを安定的に発現するNIH3T3細胞中の巨視的ΔF508−CFTR Cl−電流(IΔF508)を増加させる能力も試験した。光学的アッセイにより特定された増強因子は、光学的アッセイにおいて観察されたのと同様の効能および効力で、IΔF508の用量依存的増加を誘発した。試験したすべての細胞において、増強因子を適用する前およびその間の逆転電位は約−30mVであった。これは、計算されたEcl(−28mV)である。
ΔF508−CFTRを安定的に発現するNIH3T3マウス線維芽細胞をホールセル記録用に使用した。細胞を、175cm2培養フラスコの中で、2mMグルタミン、10%ウシ胎仔血清、1X NEAA、β−ME、1X pen/strepおよび25mM
HEPESを含むダルベッコ変法イーグル培地中、5%CO2、90%の湿度の雰囲気下、37℃で保持した。ホールセル記録のために、2,500〜5,000個の細胞を、ポリ−L−リジンコーティングしたガラスカバースリップ上に播種し、27℃で24〜48時間培養し、続いて増強因子の活性を試験するのに使用し、修正剤(corrector)の活性を測定するために、修正化合物を含むまたは含まないで、37℃でインキュベートした。
wt−CFTR、およびNIH3T3細胞で発現された温度補正ΔF508−CFTRのゲーティング活性を、Axopatch200Bパッチクランプ増幅器(Axon Instruments Inc.)を用い、既述されているようにして(Dalemans, W.、Barbry,P.、Champigny,G.、Jallat,S.、Dott,K.、Dreyer,D.、Crystal,R.G.、Pavirani,A.、Lecocq,J−P.、Lazdunski,M.(1991年)Nature 354巻、526〜528頁)、切除した内側外面型膜パッチ記録法(inside−out membrane patch recordings)を用いて観察した。ピペットは(mMで):150 NMDG、150 アスパラギン酸、5 CaCl2、2 MgCl2および10 HEPES(pHをトリス塩基で7.35に調節)を含んだ。浴は(mMで):150 NMDG−Cl、2 MgCl2、5 EGTA、10 TESおよび14 トリス塩基(pHをHClで7.35に調節)を含んだ。切除後、wt−CFTRとΔF508−CFTRの両方を、1mM Mg−ATP、75nMのcAMP依存性タンパク質キナーゼの触媒サブユニット(PKA;Promega Corp.Madison、WI)および10mM NaFを加えて活性化させてタンパク質ホスファターゼを阻害した。これは電流低下を阻止した。ピペット電位は80mVに保持された。チャネル活性は、≦2の活性チャネルを含む膜パッチから分析した。同時開口(simultaneous opening)の最大数が、実験の過程における活性チャネルの数を決定した。単一チャネル電流振幅を決定するために、120秒のΔF508−CFTR活性により記録されたデータを100Hzでフィルタリングして「オフライン」とし、Bio−Patch Analysisソフトウェア(Bio−Logic Comp.France)を用いて多重ガウス関数(multigaussian function)で当てはめた全点振幅ヒストグラムを構築するのに用いた。全微視的電流および開確率(Po)を120秒のチャネル活性から決定した。Poを、Bio−Patchソフトウェアを用いるか、関係式Po=I/i(N)(I=平均電流であり、i=単一チャネル電流振幅であり、N=パッチにおける活性チャネルの数である)を用いて決定した。
ΔF508−CFTRを安定的に発現するNIH3T3マウス線維芽細胞を、切除した膜パッチ−クランプ記録のために使用した。細胞を、175cm2培養フラスコの中で、2mMグルタミン、10%ウシ胎仔血清、1X NEAA、β−ME、1X pen/strepおよび25mM HEPESを含むダルベッコ変法イーグル培地中、5%CO2、90%の湿度の雰囲気下、37℃で保持した。単一チャネル記録のために、2,500〜5,000個の細胞を、ポリ−L−リジンコーティングしたガラスカバースリップ上に播種し、使用前に27℃で24〜48時間培養した。
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