JP2014088447A - 3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸の固体状形態 - Google Patents
3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸の固体状形態 Download PDFInfo
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- JP2014088447A JP2014088447A JP2014028062A JP2014028062A JP2014088447A JP 2014088447 A JP2014088447 A JP 2014088447A JP 2014028062 A JP2014028062 A JP 2014028062A JP 2014028062 A JP2014028062 A JP 2014028062A JP 2014088447 A JP2014088447 A JP 2014088447A
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- difluorobenzo
- dioxol
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
Description
本出願は、米国特許法§119の下、2007年12月7日に出願された米国仮特許出願第61/012,162号の利益を主張し、この出願の全内容は、本明細書中で参考として援用される。
本発明は、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸の固体状形態、例えば結晶形態、その薬学的組成物、及びそれを用いた方法に関する。
CFTRは、吸収及び分泌上皮細胞を含めて、種々の細胞タイプにおいて発現されるcAMP/ATP媒介性陰イオンチャネルであり、膜を横切る陰イオンの流れ、並びに他のイオンチャネル及びタンパク質の活性を調節する。上皮細胞では、CFTRの正常な機能は、呼吸器及び消化器組織を含めて、体全体にわたる電解質輸送の維持に重要である。CFTRは、膜貫通領域の縦列反復で構成されるタンパク質をコードする、約1480個のアミノ酸で構成され、膜貫通領域の各々が6回膜貫通ヘリックスとヌクレオチド結合領域を含む。2つの膜貫通領域は、チャネル活性及び細胞内輸送を調節する複数のリン酸化部位を有する大きな極性調節(R)領域によって連結される。
本発明は、以下の構造を有する3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸(以下、「化合物1」)の固体形態に関する。
本発明は、例えば以下の項目を提供する。
(項目1)
形態Iとして特徴づけられる3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸。
(項目2)
前記形態Iが、CuKアルファ照射によって得られたX線粉末回折における15.2から15.6度、16.1から16.5度、及び14.3から14.7度の1個以上のピークによって特徴づけられる、項目1に記載の形態I。
(項目3)
前記形態Iが15.4、16.3及び14.5度の1個以上のピークによって特徴づけられる、項目2に記載の形態I。
(項目4)
前記形態Iが14.6から15.0度のピークによって更に特徴づけられる、項目2に記載の形態I。
(項目5)
前記形態Iが14.8度のピークによって更に特徴づけられる、項目4に記載の形態I。
(項目6)
前記形態Iが17.6から18.0度のピークによって更に特徴づけられる、項目4に記載の形態I。
(項目7)
前記形態Iが17.8度のピークによって更に特徴づけられる、項目6に記載の形態I。
(項目8)
前記形態Iが16.4から16.8度のピークによって更に特徴づけられる、項目6に記載の形態I。
(項目9)
前記形態Iが16.4から16.8度のピークによって更に特徴づけられる、項目8に記載の形態I。
(項目10)
前記形態Iが16.6度のピークによって更に特徴づけられる、項目9に記載の形態I。
(項目11)
前記形態Iが7.6から8.0度のピークによって更に特徴づけられる、項目9に記載の形態I。
(項目12)
前記形態Iが7.8度のピークによって更に特徴づけられる、項目11に記載の形態I。
(項目13)
前記形態Iが25.8から26.2度のピークによって更に特徴づけられる、項目11に記載の形態I。
(項目14)
前記形態Iが26.0度のピークによって更に特徴づけられる、項目13に記載の形態I。
(項目15)
前記形態Iが21.4から21.8度のピークによって更に特徴づけられる、項目13に記載の形態I。
(項目16)
前記形態Iが21.6度のピークによって更に特徴づけられる、項目15に記載の形態I。
(項目17)
前記形態Iが23.1から23.5度のピークによって更に特徴づけられる、項目15に記載の形態I。
(項目18)
前記形態Iが23.3度のピークによって更に特徴づけられる、項目17に記載の形態I。
(項目19)
前記形態Iが、図1の回折パターンと実質的に類似した回折パターンによって特徴づけられる、項目1に記載の形態I。
(項目20)
前記形態Iが、図2の回折パターンと実質的に類似した回折パターンによって特徴づけられる、項目1に記載の形態I。
(項目21)
D90の粒径分布が約82μm以下である、項目1に記載の形態I。
(項目22)
D50の粒径分布が約30μm以下である、項目1に記載の形態I。
(項目23)
項目1に記載の形態Iと薬学的に許容される担体とを含む、薬学的組成物。
(項目24)
ほ乳動物における嚢胞性線維症を治療する方法であって、有効量の項目1に記載の形態Iを該ほ乳動物に投与することを含む、方法。
(項目25)
前記方法が、追加の治療薬を投与することを含む、項目24に記載の方法。
(項目26)
項目1に記載の形態I及びその使用説明書を含む、キット。
(項目27)
3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸のHCl塩を適切な溶媒に有効時間懸濁又は溶解させることを含む、項目1に記載の形態Iを調製するプロセス。
(項目28)
前記適切な溶媒が水又は50%メタノール/水混合物である、項目27に記載のプロセス。
(項目29)
前記適切な溶媒が水である、項目27に記載のプロセス。
(項目30)
前記有効時間が2から24時間である、項目27に記載のプロセス。
(項目31)
前記有効時間が2から6時間である、項目27に記載のプロセス。
(項目32)
単斜晶系、P21/n空間群、及び以下の単位格子寸法を有する、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸の結晶形態:
a=4.9626(7)Å α=90°
b=12.2994(18)Å β=93.938(9)°
c=33.075(4)Å γ=90°。
定義
本明細書では、別段の記載がない限り、以下の定義を適用するものとする。
一実施形態においては、形態Iは、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸のHCLなどの塩形態を適切な溶媒に有効時間分散又は溶解させて調製される。別の一実施形態においては、形態Iは、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸のHCLなどの塩形態を適切な溶媒に有効時間分散させて調製される。別の一実施形態においては、形態Iは、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)−t−ブチルベンゾアート及びギ酸などの適切な酸から直接形成される。一実施形態においては、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸のHCl塩形態が出発点であり、一実施形態においては、スキーム1〜3に従って酸塩化物部分をアミン部分とカップリングさせることによって調製することができる。
薬学的に許容される組成物
本発明の別の一態様においては、薬学的に許容される組成物が提供され、この組成物は、本明細書に記載の形態Iを含み、場合によっては、薬学的に許容される担体、補助剤又はビヒクルを含む。ある実施形態においては、この組成物は、場合によっては、1種類以上の追加の治療薬を更に含む。
更に別の一態様においては、本発明は、CFTRによって関係づけられる症状、疾患又は障害を治療する方法を提供する。ある実施形態においては、本発明は、CFTR活性の欠乏によって関係づけられる症状、疾患又は障害を治療する方法であって、本明細書に記載の形態Iの固体状形態を含む組成物をそれを必要とする対象、好ましくはほ乳動物に投与することを含む、方法を提供する。
vivo電気生理学的技術、汗若しくは唾液のCl−濃度の測定、又は細胞表面密度をモニターするex vivo生化学的若しくは組織化学的技術を使用してCFTR活性を確認する。かかる方法を使用して、最も一般的な変異であるΔF508に対して同型接合的又は異型接合的な患者を含めて、種々の異なる変異に対して異型接合的又は同型接合的な患者において残留CFTR活性を容易に検出することができる。
of Therapy;Current Opinion in Pulmonary
Medicine 6:521−529,2000)。残留CFTR活性を示す別の患者遺伝子型としては、これらのクラスの一つに対して同型接合的である患者、又はクラスI変異、クラスII変異若しくは分類されない変異を含めて、任意の他のクラスの変異と異型接合的である患者が挙げられる。
示差走査熱量測定(DSC)
形態Iの示差走査熱量測定(DSC)データをDSC Q100 V9.6 Build 290(TA Instruments、New Castle、DE)を用いて収集した。温度をインジウムを用いて較正し、熱容量をサファイアを用いて較正した。試料3〜6mgをアルミニウムパンに計量し、1個のピンホールを有する蓋を圧着した。試料を25℃から350℃まで加熱速度1.0℃/分、窒素ガスパージ50ml/分で走査した。データをThermal Advantage Q SeriesTM version 2.2.0.248ソフトウェアによって収集し、Universal Analysis software version 4.1D(TA Instruments、New Castle、DE)によって分析した。報告した数は、単一の分析結果である。
HI−STAR2次元検出器及びフラットグラファイトモノクロメーターを備えたBruker D8 DISCOVER粉末回折計によって、形態1のX線回折(XRD)データを収集した。Kα照射のCu封管を40kV、35mAで使用した。試料を25℃のゼロバックグラウンドシリコンウェーハ上に置いた。各試料について、2個のデータフレームを各々2つの異なるθ2角度8°及び26°で120秒目に収集した。データをGADDSソフトウェアによって積分し、DIFFRACTplusEVAソフトウェアによってマージした。報告したピーク位置の不確実性は±0.2度である。
酸塩化物部分
(2,2−ジフルオロ−1,3−ベンゾジオキソル−5−イル)−メタノールの合成
市販2,2−ジフルオロ−1,3−ベンゾジオキソール−5−カルボン酸(1.0当量)をトルエン(10体積)中でスラリーにする。Vitride(登録商標)(2当量)を、温度を15〜25℃に維持する速度で添加漏斗を介して添加する。添加の最後に、温度を40℃に2時間上昇させ、次いで10%(w/w)NaOH水溶液(4.0当量)を添加漏斗を介して慎重に添加し、温度を40〜50℃に維持する。更に30分間撹拌後、40℃で層分離させる。有機相を20℃に冷却し、次いで水(2×1.5体積)で洗浄し、脱水し(Na2SO4)、ろ過し、濃縮して、粗製(2,2−ジフルオロ−1,3−ベンゾジオキソル−5−イル)−メタノールを得る。それを次のステップに直接使用する。
tert−ブチル−3−(3−メチルピリジン−2−イル)ベンゾアートの合成
水及び塩基を使用した3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソル−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸(形態I)の合成
化合物のΔF508−CFTR修正特性を検出及び測定するアッセイ
化合物のΔF508−CFTR調節特性を評価する膜電位光学方法
光膜電位アッセイは、Gonzalez及びTsienによって記述された電位感受性FRETセンサー(Gonzalez,J.E.and R.Y.Tsien(1995)”Voltage sensing by fluorescence resonance energy transfer in single cells”Biophys J 69(4):1272−80、及びGonzalez,J.E.and R.Y.Tsien(1997)”Improved indicators of cell membrane potential that use fluorescence resonance energy transfer”Chem Biol 4(4):269−77参照)を、Voltage/Ion Probe Reader(VIPR)などの蛍光変化測定器と組み合わせて利用した(Gonzalez,J.E.,K.Oades,et al.(1999)”Cell−based assays
and instrumentation for screening ion−channel targets”Drug Discov Today 4(9):431−439参照)。
ΔF508−CFTRに関連する輸送欠陥を修正する小分子を特定するために、単回添加HTSアッセイ形式を開発した。試験化合物の存在下又は非存在下(負の対照)で、細胞を無血清培地中で37℃で16時間インキュベートした。正の対照として、384ウェルプレートに蒔いた細胞を27℃で16時間インキュベートして、ΔF508−CFTRを「温度修正」した。続いて、細胞をKrebs Ringers液で3回リンスし、電位感受性色素を添加した。ΔF508−CFTRを活性化するために、10μMフォルスコリン及びCFTR増強物質ゲニステイン(20μM)をCl−非含有培地と一緒に各ウェルに添加した。Cl−非含有培地の添加は、ΔF508−CFTRの活性化に応答してCl−流出を促進した。生じた膜脱分極を、FRETに基づく電圧センサー色素を使用して光学的にモニターした。
ΔF508−CFTRの増強物質を特定するために、2回添加HTSアッセイ形式を開発した。最初の添加中に、試験化合物を含む又は含まないCl−非含有培地を各ウェルに添加した。22秒後、2〜10μMフォルスコリンを含むCl−非含有培地の第2の添加分を添加して、ΔF508−CFTRを活性化した。両方の添加後の細胞外Cl−濃度は28mMであり、ΔF508−CFTR活性化に応答してCl−流出を促進した。生じた膜脱分極を、FRETに基づく電圧センサー色素を使用して光学的にモニターした。
浴溶液#1:(mM)NaCl 160、KCl 4.5、CaCl2 2、MgCl2 1、HEPES 10、NaOHを用いてpH7.4
塩化物イオン非含有浴溶液:浴溶液#1中の塩化物塩をグルコン酸塩で置換する。
ΔF508−CFTRを安定に発現するNIH3T3マウス線維芽細胞を膜電位の光学的測定に使用する。175cm2培養フラスコ中の2mMグルタミン、10%ウシ胎仔血清、1×NEAA、β−ME、1×pen/strep及び25mM HEPESを補充したダルベッコ変法イーグル培地中で37℃、5%CO2及び湿度90%で細胞を維持する。すべての光学的アッセイについて、384ウェルmatrigel被覆プレート中に細胞を30,000個/ウェルで蒔き、37℃で2時間培養後、増強物質アッセイのために27℃で24時間培養した。修正アッセイのために、細胞を27℃又は37℃で化合物と一緒に、さらに、化合物なしで、16〜24時間培養する。
1.チャンバーアッセイの使用
チャンバー実験の使用を、ΔF508−CFTRを発現する分極された上皮細胞について実施して、光学的アッセイにおいて特定されたΔF508−CFTR調節物質を更に特徴づけた。Costar Snapwell細胞培養挿入物上で成長させたFRTΔF508−CFTR上皮細胞をUssingチャンバー(Physiologic Instruments,Inc.、San Diego、CA)に取り付け、電位固定システム(Department of Bioengineering,University
of Iowa,IA及びPhysiologic Instruments,Inc.、San Diego、CA)を使用して単層を連続的に短絡させた。経上皮の抵抗を2mVパルスを印加して測定した。これらの条件下で、FRT上皮は4KΩ/cm2以上の抵抗を示した。溶液を27℃で維持し、空気をバブリングさせた。電極オフセット電位及び流体抵抗を、無細胞挿入物を使用して補正した。これらの条件下で、電流は、頂端膜において発現されるΔF508−CFTRを介したCl−の流れを反映する。MP100A−CEインターフェース及びAcqKnowledgeソフトウェア(v3.2.6;BIOPAC Systems、Santa Barbara、CA)を使用して、ISCをデジタル方式で取得した。
典型的なプロトコルは、側底から頂端膜のCl−濃度勾配を利用した。この勾配を設定するために、正常リンゲル液を側底膜に使用し、一方、頂端側NaClを等モルの(NaOHでpH7.4に滴定された)グルコン酸ナトリウムで置換して、上皮を横切る大きいCl−濃度勾配を得た。すべての実験を無処置単層を用いて実施した。ΔF508−CFTRを十分に活性化するために、フォルスコリン(10μM)及びPDE阻害剤IBMX(100μM)を適用し、続いてCFTR増強物質ゲニステイン(50μM)を添加した。
典型的なプロトコルは、側底から頂端膜のCl−濃度勾配を利用した。この勾配を設定するために、正常リンゲル液を側底膜に使用し、ナイスタチン(360μg/ml)で透過性にし、一方、頂端側NaClを等モルの(NaOHでpH7.4に滴定された)グルコン酸ナトリウムで置換して、上皮を横切る大きいCl−濃度勾配を得た。すべての実験をナイスタチン透過化処理の30分後に実施した。フォルスコリン(10μM)及びすべての試験化合物を細胞培養挿入物の両側に添加した。推定上のΔF508−CFTR増強物質の有効性を、公知の増強物質ゲニステインの有効性と比較した。
側底溶液(mM):NaCl(135)、CaCl2(1.2)、MgCl2(1.2)、K2HPO4(2.4)、KHPO4(0.6)、N−2−ヒドロキシエチルピペラジン−N’−2−エタンスルホン酸(HEPES)(10)及びデキストロース(10)。NaOHを使用して溶液をpH7.4に滴定した。
ΔF508−CFTRを発現するFisherラット上皮(FRT)細胞(FRTΔF508−CFTR)を、本発明者らによる光学的アッセイから特定された推定ΔF508−CFTR調節物質のUssingチャンバー実験に使用した。細胞をCostar Snapwell細胞培養挿入物上で培養し、5%ウシ胎仔血清、100U/mlペニシリン及び100μg/mlストレプトマイシンを補充したCoon改変Ham F−12培地中で37℃及び5%CO2で5日間培養した。化合物の増強物質活性を特徴づけるのに使用する前に、細胞を27℃で16〜48時間インキュベートして、ΔF508−CFTRを修正した。修正化合物の活性を求めるために、細胞を27℃又は37℃で化合物と一緒に、さらに、化合物なしで、24時間インキュベートした。
ΔF508−CFTRを安定に発現する、温度及び試験化合物で修正されたNIH3T3細胞における巨視的ΔF508−CFTR電流(IΔF508)を、穿孔パッチホールセル記録を使用してモニターした。手短に述べると、IΔF508の電位固定記録を、Axopatch 200Bパッチクランプ増幅器(Axon Instruments Inc.、Foster City、CA)を用いて室温で実施した。すべての記録をサンプリング周波数10kHzで取得し、1kHzの低域フィルターにかけた。ピペットは、細胞内液で満たすと5〜6MΩの抵抗を有した。これらの記録条件下で、室温でのCl−の計算逆転電位(ECl)は−28mVであった。すべての記録は、シール抵抗>20GΩ及び直列抵抗<15MΩであった。パルス発生、データ取得及び分析を、Clampex 8に接続されたDigidata 1320 A/Dインターフェースを備えたPC(Axon Instruments Inc.)を使用して実施した。浴は、食塩水<250μlを含み、重力駆動の潅流システムを使用して速度2ml/分で連続的に洗い流した。
原形質膜中の機能的ΔF508−CFTRの密度を増加させる修正化合物の活性を求めるために、本発明者らは、上記穿孔パッチ記録技術を使用して、修正化合物で24時間処理した後の電流密度を測定した。ΔF508−CFTRを十分に活性化するために、10μMフォルスコリン及び20μMゲニステインを細胞に添加した。本発明者らの記録条件下では、27℃で24時間インキュベートした後の電流密度は、37℃で24時間インキュベートした後に観察された電流密度より高かった。これらの結果は、原形質膜中の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求めるために、細胞を10μM試験化合物と一緒に37℃で24時間インキュベートし、電流密度を27℃及び37℃の対照と比較した(%活性)。記録前に、細胞を細胞外記録培地で3回洗浄して、残留試験化合物を除去した。10μM修正化合物と一緒にプレインキュベートすると、cAMP及びゲニステインに依存性した電流が37℃の対照に比べてかなり増加した。
ΔF508−CFTRを安定に発現するNIH3T3細胞において巨視的ΔF508−CFTR Cl−電流(IΔF508)を増加させるΔF508−CFTR増強物質の能力も穿孔パッチ記録技術を用いて調べた。光学的アッセイから特定された増強物質は、光学的アッセイにおいて認められた類似の作用強度及び効力でIΔF508の用量依存的増加を惹起した。試験したすべての細胞において、増強物質の適用前及び適用中の逆転電位は、約−30mVであった。約−30mVは、計算したECl(−28mV)である。
細胞内液(mM):アスパラギン酸Cs(90)、CsCl(50)、MgCl2(1)、HEPES(10)及び240μg/mlアンホテリシンB(CsOHを用いて7.35に調節されたpH)。
ΔF508−CFTRを安定に発現するNIH3T3マウス線維芽細胞をホールセル記録に使用する。175cm2培養フラスコ中の2mMグルタミン、10%ウシ胎仔血清、1×NEAA、β−ME、1×pen/strep及び25mM HEPESを補充したダルベッコ変法イーグル培地中で37℃、5%CO2及び湿度90%で細胞を維持する。ホールセル記録の場合、2,500〜5,000個の細胞をポリ−L−リジン被覆カバーガラス上に蒔き、27℃で24〜48時間培養した後、増強物質の活性を試験するのに使用した。さらに、修正化合物と一緒に、又は修正化合物なしで、37℃でインキュベートして、修正化合物の活性を測定した。
NIH3T3細胞中で安定に発現された温度修正ΔF508−CFTRの単一チャネル活性、及び増強物質化合物の活性を、切り出したインサイドアウト膜パッチを使用して観察した。手短に述べると、単一チャネル活性の電位固定記録を、Axopatch 200Bパッチクランプ増幅器(Axon Instruments Inc.)を用いて室温で実施した。すべての記録をサンプリング周波数10kHzで取得し、400Hzの低域フィルターにかけた。パッチピペットは、Corning Kovar Sealing#7052ガラス(World Precision Instruments,Inc.、Sarasota、FL)から作製され、細胞外液で満たしたときに5〜8MΩの抵抗を有した。切り出し後に1mM Mg−ATP及び75nM cAMP依存性タンパク質キナーゼ触媒サブユニット(PKA;Promega Corp.Madison、WI)を添加することによってΔF508−CFTRを活性化した。チャネル活性が安定化された後、重力駆動微小潅流システムを使用してパッチを洗い流した。流入液をパッチに隣接して置き、1〜2秒以内に溶液を完全に交換した。急速な洗い流し中にΔF508−CFTR活性を維持するために、非特異的ホスファターゼ阻害剤F−(10mM NaF)を浴溶液に添加した。これらの記録条件下で、チャネル活性は、パッチ記録の期間(最高60分間)を通して一定のままであった。細胞内液から細胞外液に移動する陽電荷(反対方向に移動する陰イオン)によって生成される電流を正電流として示す。ピペット電位(Vp)を80mVで維持した。
細胞外液(mM):NMDG(150)、アスパラギン酸(150)、CaCl2(5)、MgCl2(2)及びHEPES(10)(Tris塩基を用いて7.35に調節されたpH)。
ΔF508−CFTRを安定に発現するNIH3T3マウス線維芽細胞を、切り出された膜のパッチクランプ記録に使用する。175cm2培養フラスコ中の2mMグルタミン、10%ウシ胎仔血清、1×NEAA、β−ME、1×pen/strep及び25mM
HEPESを補充したダルベッコ変法イーグル培地中で37℃、5%CO2及び湿度90%で細胞を維持する。単一チャネル記録の場合、2,500〜5,000個の細胞をポリ−L−リジン被覆カバーガラス上に蒔き、使用前に27℃で24〜48時間培養した。
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