JP2014513717A - 生体直交型薬物活性化 - Google Patents
生体直交型薬物活性化 Download PDFInfo
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- JP2014513717A JP2014513717A JP2014510930A JP2014510930A JP2014513717A JP 2014513717 A JP2014513717 A JP 2014513717A JP 2014510930 A JP2014510930 A JP 2014510930A JP 2014510930 A JP2014510930 A JP 2014510930A JP 2014513717 A JP2014513717 A JP 2014513717A
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- A—HUMAN NECESSITIES
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Abstract
Description
プロドラッグの投与及び活性化に関するキットであって、当該キットは、
トリガー部分に、直接的に又は非直接的に結合された薬物、及び前記トリガー部分に関するアクチベータを含み、
前記トリガー部分は、ジエノフィルを含み、
前記アクチベータは、ジエンを含み、
前記ジエノフィルは、下記式(1a)を満たす:
キット。
(1)結合PQ、QP、QX、XQ、XZ、ZX、ZY、YZ、YA、AYの1つは、−CRaXD−CRaYD−から構成され、A、Y、Z、X、Q、Pによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDはO−C(O)−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)であり;かつYDはNHRc、OH、SHであり;又はXDはC(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;かつYDはCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2又はNH−OHである;
(2)AはCRaXDでありかつZはCRaYDである、又はZはCRaXDでありかつAはCRaYDである、又は、PはCRaXDでありかつXはCRaYDである、又はXはCRaXDでありかつPはCRaYDであり、XD及びYDは互いに関連してトランス型に配置され;A、Y、Z、X、Q、及びPによって構成される残基は、互いに独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDは、O−C(O)−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)であり、かつYDはNHRc、OH、SH、CRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2又はNH−OHである;又はXDはCRc 2−O−C(O)−(LD)n−(DD)、CRc 2−S−C(O)−(LD)n−(DD)、CRc 2−O−C(S)−(LD)n−(DD)、CRc 2−S−C(S)−(LD)n−(DD)、CRc 2−NRc−C(O)−(LD)n−(DD)、CRc 2−NRc−C(S)−(LD)n−(DD)であり、かつYDはNHRc、OH、SHである;又はXDはC(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;かつYDはCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2、NH−OHである;
(3)AはCRaYDであり、かつ、P、Q、X、Zの1つはCRaXDであり、又は、PはCRaYD であり、かつ、A、Y、Z、Xの1つはCRaXDである、又はYはCRaYD であり、かつX又はPはCRaXDである、又は、QはCRaYDであり、かつ、Z又はAはCRaXDである、又は、Z又はXのいずれかはCRaYDであり、かつ、A又はPはCRaXDであり、XD及びYDは互いに関連してトランス型に配置され;A、Y、Z、X、Q及びPによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びA はCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sを構成する群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し; XDは(O−C(O))p−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)であり、YDはCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2、NH−OHであり; pは0又は1である;
(4)PはCRaYDであり、かつ、YはCRaXDである、又はAはCRaYDであり、かつ、QはCRaXDである、又はQはCRaYDであり、かつ、AはCRaXDである、又はYはCRaYDであり、かつPはCRaXDであり、XD及びYDは、互いに関連してトランス型に配置され;A、Y、Z、X、Q及びPから構成される残基は、互いに独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し; XDは(O−C(O))p−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)であり;YDはNHRc、OH、SHであり;pは0又は1である;
(5)YはYDであり、かつ、PはCRaXDである、又はQはYDであり、かつ、AはCRaXDであり;A、Y、Z、X、Q及びPによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDは(O−C(O))p−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)、C(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;YDはNHであり; pは0又は1である;
(6)YはYDであり、かつ、P又はQはXDである、又は、QはYDであり、かつ、A又はYはXDであり;A、Y、Z、X、Q及びPによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S、及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDはN−C(O)−(LD)n−(DD)、N−C(S)−(LD)n−(DD)であり;YDはNHであり;
ここで、各々のRaは、独立して、H、アルキル、アリール、OR’、SR’、S(=O)R’’’、S(=O)2R’’’、S(=O)2NR’R’’、Si−R’’’、Si−O−R’’’、OC(=O)R’’’、SC(=O)R’’’、OC(=S)R’’’、SC(=S)R’’’、F、Cl、Br、I、N3、SO2H、SO3H、SO4H、PO3H、PO4H、NO、NO2、CN、OCN、SCN、NCO、NCS、CF3、CF2−R’、NR’R”、C(=O)R’、C(=S)R’、C(=O)O−R’、C(=S)O−R’、C(=O)S−R’、C(=S)S−R’、C(=O)NR’R”、C(=S)NR’R’’、NR’C(=O)−R’’’、NR’C(=S)−R’’’、NR’C(=O)O−R’’’、NR’C(=S)O−R’’’、NR’C(=O)S−R’’’、NR’C(=S)S−R’’’、OC(=O)NR’−R’’’、SC(=O)NR’−R’’’、OC(=S)NR’−R’’’、SC(=S)NR’−R’’’、NR’C(=O)NR’’−R’’、NR’C(=S)NR’’−R’’、CR’NR’’から構成される群から選択され、各々のR’及び各々のR’’は、独立して、H、アリール又はアルキルであり、R’’’は、独立して、アリール又はアルキルであり;各々のRbは、独立して、H、アルキル、アリール、O−アルキル、O−アリール、OHから構成される群から選択され;各々のRcは、独立して、H、C1−6アルキル及びC1−6アリールから選択され; 2つ以上のRa,b,c部分は、結合して環を形成しても良く; 及び(LD)nは、好ましくはS、N、NH又はOを介してTRに結合された、n= 0又は1を有する任意のリンカーであり、ここで、これらS、N、NH又はO原子はリンカーの一部であり、直鎖状に及び/又は分枝状に配置された複数のユニットを構成しても良く;DDは、好ましくはS、N、NH又はOを介して結合された1つ以上の治療的部分又は薬物であり、ここでこれらS、N、NH又はO原子は、前記治療的部分の一部である)、を供する。
式(1a)のジエノフィルとジエンとは、逆電子要請型ディールスアルダー反応の可能性を有する。トリガーのアクチベータとのレトロディールスアルダー反応によるプロドラッグの活性化は、薬物の放出を導く。
スキーム1:
ここで、「アルキル」は、それぞれ独立して、10炭素原子までの脂肪族、直鎖、分岐、飽和、不飽和及び/又は環状ヒドロカルビル基を示し、1〜10のO、N又はSなどのヘテロ原子を含むことができ、「アリール」は、それぞれ独立して、20炭素原子までの芳香族基又はヘテロ芳香族基を示し、置換されていてよく、及び1〜10のO、N又はSなどのヘテロ原子を含むことができる。「アリール」基はまた、「アルキルアリール」又は「アリールアルキル」基(簡単な例ではベンジル基)を含む。「アルキル」、「アリール」、「アルキルアリール」及び「アリールアルキル」が含む炭素原子の数は、かかる用語の前に指定されることで示される(即ち、C1−10アルキルは、前記アルキルが1から10の炭素原子を含み得ることを意味する)。本発明のある化合物は、キラル中心及び互変異性体を含み、及び全てのエナンチオマー、ジアステレオマー及び互変異性は、それらの混合物も含めて本発明の範囲に含まれる。いくつかの式で、基又は置換基は、「A」、「B」、「X」、「Y」などの文字で参照され、種々の(数字付き)「R」基で参照される。これらの文字の定義は、各々の式について読まれるべきものであり、即ち異なる式ではこれらの文字は特に断りがない限り、それぞれ独立して、異なる意味を持ち得る。
レトロディールスアルダーカップリング化学は、一般的に、一組の反応物がカップリングして不安定な中間体を形成し、この中間体がレトロディールスアルダー反応による唯一の副生成物として小分子(出発原料に依存して、これは例えば、N2、CO2、RCNになり得る)を放出して、レトロディールスアルダー付加物を形成する。一組の反応物は、1つの反応物として(即ち1つの生体直交型反応基)、例えば電子不足テトラジンなどのテトラジン誘導体といった好適なジエン及び、他の反応物として(即ち、他の生体直交型反応基)、歪ずみのかかったシクロオクテン(TCO)といった適切なジエノフィルを含む。
プロドラッグは、TRとして示されるトリガー部分に、直接的に又は間接的に、結合されたDDとして示される薬物を含み、前記トリガー部分はジエノフィルである。ジエノフィルは、広い意味で、8員環非芳香族性環アルケニレン部分(好ましくはシクロオクテン部分、及びより好ましくはトランス−シクロオクテン部分)である。
前記示される各々のRbは独立して、H, アルキル, アリール, O−アルキル, O−アリール, OHからなる群から選択され;
前記示される各々のRcは独立して、H, C1−6アルキル及びC1−6アリールから選択され;
2以上のRa’b’c部分は共に環を形成し得;
好ましくは、各々のRaは独立して、H、アルキル、O−アルキル、O−アリール、OH、C(=O)NR’R’’、NR’C(=O)−R’’’からなる群から選択され、R’及びR’’は各々独立してH、アリール又はアルキルであり、R’’’は独立してアルキル又は又はアリールである。
本発明はまた、全ての実施形態において、式(1a)を満たすトランス−シクロオクテンの、治療用化合物のキャリアとしての使用を含む。トランスシクロオクテンは、上述されるように、広い意味でTCOとして記載されており、好ましくは全ての炭素環又は1又は2のヘテロ原子を含む。治療用化合物は、薬物又はその他の化合物又は治療応用を有することが意図されている部分である。本発明のこの側面に係るキャリアとしてのTCOの使用は、治療用化合物の治療活性とは関連しない。実際に、また、治療用化合物が薬物として開発されることが意図される薬物質である場合、多くの場合には実際には失敗し得るものであるが、キャリアとしてのTCOの応用は、薬物の試験において有用である。この意味で、キャリアの許容性でのTCOは、医薬賦形剤と同様であると考えられ、薬物を被験者に導入する場合にキャリアとして作用する。
アクチベータは、生体直交型反応基を含み、このアクチベータの生体直交型反応基はジエンである。このジエンは、他の生体直行型反応基、トリガー、ここではジエノフィルと反応する(上記参照)。アクチベータのジエンは、レトロディールスアルダー付加物を与える、レトロディールスアルダー反応に続く、ディールスアルダーシクロ付加反応を経る、トリガーのジエノフィルとの反応を可能にするように選択される。この中間的付加物は、その後、1以上の薬物を放出するが、この薬物放出は、レトロディールスアルダー付加物の特定の分子構造に関連する、種々の環境や条件下で引き起こされ得る。
当業者は、レトロディールスアルダー反応で活性であるジエンの効果(wealth)に気付く。アクチベータ内に含まれるジエンは、テトラジン(本発明に係る好ましいアクチベータである)等の第3の二重結合を含む環構造の部分であり得る。
上記において、アクチベータは、本発明のどちらの2つの好ましい実施形態に関しても述べられ、定義されており、両方の実施形態に関して、1,2−ジアジン、1,2,4−トリアジン及び1,2,4,5−テトラジン、具体的には1,2,4,5−テトラジンが好ましいジエンアクチベータである。下記において、アクチベータのいくつかの関連する特徴が強調され、ここで全ての特定の用途に関して正しいアクチベータ剤を設計するために、多くの選択肢があるということが明らかになるであろう。
プロドラッグは、薬物DD及びトリガーTRの共役物であり、したがって、トリガーから放出後の治療作用が可能になる薬物を含む。そのようなプロドラッグは、場合により、疾患標的に特異性を有する。
式(8a):k=1;m,r≧1;t,n≧0;
式(8b):k=1;m,n,r≧1;t≧0である。
式(8a)及び(8b):r=1;m≧1;k,n,t≧0である。
次のスキームは、rDA反応に関する選択に基づき、プロドラッグの活性化に適用され得る種々のメカニズムを説明するための、非制限的な例を示す。留意すべきことは、アミン官能性薬物の放出の場合において、これらは、例えば、一級又は二級アミン、アニリン、イミダゾール又はピロールタイプの薬物であり、薬物は、脱離基の性質で変わり得るということである。対応する加水分解に安定なTCOプロドラッグが適用される場合には、他の官能基を有する薬物の放出も、起こり得る(例えば、チオール官能性薬物)。示される縮合環生成物は、他のより好ましい互変異性体に対して互変異性であっても良いし、そうでなくても良い。
本発明のキット及び方法は、薬物の標的化送達での使用に非常に適する。
マスキング部分MMは、タンパク質、ペプチド、ポリマー、ポリエチレングリコール、炭水化物、有機構成物であり得、これらは更に、結合された薬物DD又はプロドラッグを封止する。この封止は、例えば立体障害に基づくものであり得るが、薬物DDとの非共有結合相互作用に基づくものであっても良い。このようなマスキング部分はまた、DD又はプロドラッグのインビボ特性(例えば血液からの除去;免疫系による認識)に影響を及ぼすように使用され得る。
スペーサーSPは、限定されないが、2から200までの、具体的には3から113までの、好ましくは5から50までの繰り返し単位で変わる、ポリエチレングリコール(PEG)鎖を含む。他の例は、オリゴ又はポリペプチド又はポリアクチド等の生体ポリマー断片である。更に好ましい例は、例9で示される。
本発明のコンテクストにおいて、プロドラッグは通常は最初に投与され、ある時間後に、プロドラッグが第1の標的に到達する。この時間間隔は応用により異なり、分から日又は週に亘り得る。選択された時間が経過した後、アクチベータが投与され、これは、プロドラッグを見つけて反応し、それにより第1の標的で薬物放出を活性化する。
以下の実施例は、本発明又は本発明の側面を説明するものであり、本発明の範囲又は特許請求の範囲を定め又は限定するものではない。
1H−NMR及び13C−NMRスペクトルはVarian Mercury(1H−NMRは100MHzで、13C−NMRは400MHzで測定)スペクトル装置を用いて298Kで記録された。化学シフトは、室温で、TMSから下方磁場へのppm(ppm downfield)において記録される。分裂パターンに関して使用される略号は、s=シングレット、d=ダブレット、t=トリプレット、q=カルテット、m=マルチプレット及びbr=ブロードである。Irスペクトルは、Perkin Elmer1600FT−IR(UATR)で記録された。LC−MSは、Shimadzu LC−10 AD VPシリーズHPLCで、ダイオードアレイ検出器(Finnigan Surveyor PDA Plus detector、Thermo Electron Corporation)及びIon−Trap(LCQ Fleet、Thermo Scientific)を用いて記録された。分析は、Alltech Alltima HPC183μカラムを用いて、注入容量1−4μLとし、流速は0.2mL/分及び通常は、25℃で、H2O中CH3CN(共に0.1%ギ酸を含む)のグラジエント(5%から100%へ10分間で、100%でさらに3分間保持)を用いて行った。分取用RP−HPLC(0.1%ギ酸CH3CN/H2O)を、Phenomenex Gemini5μC18110Aカラムで、Shimadzu SCL−10A VPと2つのShimadzu LC−8Aポンプ及びShimadzu SPD−10AV VP紫外−可視光検出器を用いて行った。サイズ排除(SEC)HPLCは、Agilent 1200システムとGabi放射線検出器を用いて行った。サンプルは、Superdex−200 10/300 GLカラム(GE Healthcare Life Sciences)に負荷し、10mMのリン酸緩衝液、pH7.4で0.35〜0.5mL/分で溶出させた。UV波長は260nmと280nmに設定した。抗体溶液の濃度は、NanoDrop 1000 spectrophotometer(Thermo Fisher Scientific)を用いて、322nm及び280nmでのそれぞれの吸光度から決定された。
全ての試薬、化学物、材料及び溶媒は、市販品から入手しそのまま使用した:(重水素化)溶媒は、Biosolve、Merck and Cambridge Isotope Laboratoriesから;及び化学物、材料及び試薬は、Aldrich、Acros、ABCR、Merck及びFlukaから入手した。全ての溶媒は、AR品質であった。4−(t−ブチルジメチルシリルオキシメチル)−2,6−ジメチルフェノールは文献の手順に従って合成した(Y.H.Choe、C.D.Conover、D.Wu、M.Royzen、Y.Gervacio、V.Borowski、M.Mehlig、R.B.Greenwald、J.Controlled Release2002、79、55−70)。ドキソルビシン塩化水素はAvachem Scientificから入手した。
テトラジンアクチベータの合成
一般的手順
以下に詳細に説明されるテトラジンとは別に、一連の他のテトラジンが準備された。ピナー型反応が使用され、適当なニトリルをヒドラジンと反応させ、ジヒドロ1,2,4,5−テトラジン中間体を合成した。当該分野で知られているように、ニトリルの代わりに、アミジンも反応物として使用されている。この反応で硫黄の使用も知られており、ある場合には、これにより、1,2,4,5−テトラジンの形成を促進される。この中間体の酸化によりテトラジンジエンアクチベータが得られる。下記反応は、いくつかの合成されたテトラジン及びテトラジンの合成及び単離可能性を説明する(例えば、溶媒、濃度、温度、反応物の当量、酸化反応の選択、等)。当該分野で知られる他の反応も、テトラジン又は他のアクチベータを製造するために使用されても良い。
アセタミド4(50mg、0.169mmol)を酢酸(1mL))に分散させ、亜硝酸ナトリウム(35mg;0.508mmol)を添加した。すぐにオレンジ色から暗赤色への色変化が観測され、酸化生成物をろ過して分離した。残渣を水(5mL)で洗浄し、真空で乾燥して、表記の化合物を紫色固体として得た(5、42mg;84%)。
PET)で有用である。結果として、アクチベータ29は、薬物放出に好適のみならず、同時にイメージング目的でも使用され得る。事実、アクチベータ29は、111In3+と錯体化後、SPECT/CTイメージングプローブとして使用されてきた。さらに詳細については、Robillardらの文献を参照のこと(Angew.Chem.,2010,122,3447−3450)。
(E)−シクロオクテンモデルプロドラッグ及びプロドラッグの合成
シス−(E)−シクロオクタ−5−エン−1,2−ジアミン(35)の合成
m/z=288(M+H+),lmax=243 nm:10.9 mgの主異性体(23%収率)及び1.9 mgの副異性体(4%収率)で得た。
(E)−シクロオクテン−ドキソルビシン共役物68の合成
例3
テトラジンアクチベータの安定性及び反応性
テトラジンの加水分解安定性試験
特定のテトラジンのDMSO(25mM)溶液の10μLをPBS緩衝液(3mL)(又は、水溶性があまりに小さい場合には、PBS及びアセトニトリルの混合物)に希釈した。この溶液をろ過し、525nmでの吸収バンドの減少を、UVスペクトル計を使用して測定した。加水分解の速度及び半減期をこれらのデータから決定した。
競争実験を実施して、特定のテトラジンと3−(5−アセタミド−2−ピリジル)−6−(2−ピリジル)−1,2,4,5−テトラジン(参考テトラジンとして選択された)との、トランス−シクロオクタ−4−エン−1−オール(アキシャル位置でのOHを有する「副」異性体:WhithamらのJ.Chem.Soc.(C)、1971,883−896を参照)との逆電子要請型ディールスアルダー反応での、反応比率を決定した。
トランス−シクロオクテンモデルプロドラッグ及びプロドラッグの安定性と反応性
安定性
10μLの特定のトランス−シクロオクテン誘導体のジオキサン(25mM)溶液をPBS緩衝液(3mL)で希釈し、この溶液を暗所、20℃で保存した。TCO化合物の運命(fate)をHPLC−MS分析で測定し、モデルのプロドラッグの放出に基づいて半減期を評価した。
トランス−シクロオクテン誘導体の3−(5−アセトアミド−2−ピリジル)−6−(2−ピリジル)−1,2,4,5−テトラジンとの、アセトニトリル中20℃で実行された、逆電子要請型ディールスアルダー反応の速度論を、UV−可視スペクトル装置を用いて決定した。キュベットをアセトニトリル(3mL)で満たし20℃で平衡した。3−(5−アセトアミド−2−ピリジル)−6−(2−ピリジル)−1,2,4,5−テトラジン(2.50´10−7mol)を添加し、次にトランス−シクロオクテン誘導体(2.50×10−7mol)を添加した。λ=540nmでの吸収の減衰をモニターし、この曲線から二次反応速度定数k2を、二次反応速度論を仮定して決定した。
競争反応
競争反応を、特定のトランス−シクロオクテン誘導体と、トランス−シクロオクタ−4−エン−1−オール(アキシャル異性体)(これはトランス−シクロオクテンの参照として選択された)との、ビス(2−ピリジル)−1,2,4,5−テトラジンとの逆電子要請型ディールスアルダーでの反応比を決定するために実行した。
**競争実験によって決定した。
モデルプロドラッグの活性化(アクティベーション)
((E)−8−アミノシクロオクタ−4−エン−1−イル)カーバメート(36)
ドキソルビシンプロドラッグの活性化(アクティベーション)
3,6−ビス(2−ピリジニル)−1,2,4,5−テトラジン(2)及び(E)−シクロオクテン−ドキソルビシン共役物(64)
−(E)−シクロオクテン−ドキソルビシン共役物(64,2.67×10−5g;2.50×10−8mol)を添加した。溶液を20℃で撹拌し、反応進行をHPLC−MS分析でモニタし、m/z=+375Da(M+H+)を有する環状ウレアの形成、及びドキソルビシン:m/z=+544Da(M+H+)及びλmax=478nmの放出がわかった。この放出の半減期は2時間だった。
ドキソルビシンプロドラッグ64及びテトラジン29との細胞増殖アッセイ
A431扁平上皮癌細胞を、10%熱不活性化ウシ胎児血清及びペニシリン及びストレプトマイシン存在0.05%グルタマックス(Invitrogen)を添加したDMEM(Invitrogen)中で、37℃で、加湿CO2インキュベーター内に維持された。実験を開始する24時間前に、細胞を96ウェルプレート(Nunc)に、2000細胞/ウェル密度で植えた。ドキソルビシン(Dox)及びプロドラッグ64(DMSO中1mM)を、実験開始及びウェルに添加する直前に、加温培地内で連続希釈された(最終容積は200μl;t=0)。プロドラッグを、単独又は10μMテトラジン29との組み合わせのいずれかで添加された。37℃で6時間インキュベーション後、培地を静かに吸い取り、200μLの新しい培地を各々のウェルに添加し、細胞を更に66時間以上インキュベーションした。並列実験において、テトラジン29の溶液(PBS中2mM)を加温培地内で連続希釈し、96ウェルプレート内のA431細胞に添加し、37℃で72時間インキュベーションした。各々の実験の終了後、細胞増殖をMTTアッセイによって評価した。簡単には、メチルチアゾリルジフェニルテトラゾリウムブロミド(MTT)を5mg/mlでPBSに溶解し、0.22μmを通じてろ過し、25μLを各々のウェルに添加した。37℃での120分のインキュベーション後、培地をゆっくり吸い取った。形成されたホルマザン結晶を100μlDMSOにときに、溶解し、吸収を560nmでプレートリーダー(BMG Labtech)で、測定した。IC50値(±標準偏差、表参照)を、GraphPad Prism(version5.01)を用いて作成した標準細胞成長曲線(図参照)から誘導した。細胞増殖アッセイは、A431細胞がプロドラッグ単体(IC50=128±17nM)又はテトラジン29(IC50>100μM)と比して、プロドラッグ64及びテトラジン29の組み合わせに曝された時に、重大な毒性増大を示す。これは、ドキソルビシンが放出され、続いてプロドラッグのトランス−シクロオクテンとテトラジンアクチベータとのディールスアルダー反応を確認する。
例8
例示的なL D 部分の構造
例示的なS P 部分の構造
留意すべきことは、マレイミド、活性エステル及びブロモアセトアミド基は、目標部分TT及びマスキング部分MMが、場合によっては更なるスペーサーSPを介して結合され得る活性基であるということである。マレイミド及びブロモアセトアミド基は、通常、チオールと反応し、活性エステルは、通常、一級又は二級アミンにカップリングするに公的である。
例示されたL D 部分を有するTCOトリガーの構造
この例で示されるTTは、場合によってMMによって置換されても良い。
例示されたL D 部分及び/又はS P 部分を有するTCOトリガーの構造
トリガーは、TTのアミン又はチオールを介してTTに共役した。この例で示されたTTは、場合によってMMによって置換されても良い。
抗体−薬物共役物の構造
アウリスタチンE(MMAE)トキシンを、自壊性リンカーLDを介してTCOトリガーに結合し、及びSPを介して標的抗体又は断片(システイン又はリジン残基を介して共役)に結合される。Ab=抗体又は抗体断片;q=Ab変性#であり、通常は#は1と10の間である。
抗体−薬物共役物の構造
メイタンシントキシンを、自壊性リンカーLDを介してTCOトリガーに結合し、及びSPを介して標的抗体又は断片(システイン又はリジン残基を介して共役)に結合される。Ab=抗体又は抗体断片;q=Ab変性#であり、通常は#は1と10の間である。
アミン又はチオール部分を介して標的試薬T T 等に共役され得るトリガー−薬物構成物の構造
アウリスタチンE(MMAE)トキシンを、自壊性リンカーLDを介してTCOトリガーに結合し、及びSPを介してTT共役物のための反応部分に結合される。
アミン又はチオール部分を介して標的試薬T T 等に共役され得るトリガー−薬物構成物の構造
メイタンシントキシンを、自壊性リンカーLDを介してTCOトリガーに結合し、及びSPを介してTT共役物のための反応部分に結合される。
腫瘍結合CC49−アウリスタチンE共役物の活性化
mAb又はmAb断片としてのCC49は、非内在化汎固形腫瘍マーカーTAG72へ結合する。プロドラッグ投与、腫瘍結合及び血液から除去後、アクチベータが注入される。アクチベータのTCOトリガーとの、プロドラッグ中での反応の結果、アウリスタチンEをCC49(抗体又は抗体断片)から放出し、これはがん細胞を浸透して抗癌作用を発揮する。
腫瘍結合T−細胞係合三抗体の活性化
三抗体は、腫瘍−結合部分、CD3T−細胞係合部分、及びCD28T−細胞共刺激部分を含む。1つの分子に結合されたCD3及びCD28が標的に許容されない毒性効果を生じる結果となり、抗−CD28ドメインはマスキング部分MMでブロックされ、これはCD28結合ドメインに類似するペプチドであり、抗−CD28部分への親和性を持つ。このペプチドは、更なるペプチド又はPEG鎖SPを通じてTCOトリガーに結合され、これ自体が、特別に設計されたシステインサイトへ共役されている。プロドラッグ投与、腫瘍結合及び血液からの除去後、アクチベータが注入される。アクチベータのプロドラッグ内のTCOトリガーとの反応は、抗−CD28ドメインからマスキング部分を放出し、T−細胞のCD28共刺激を可能とし、T−細胞介在抗癌作用を促進し、標的への毒性を防止する。
Claims (21)
- プロドラッグの投与及び活性化に関するキットであって、当該キットは、
トリガー部分に、直接的に又は非直接的に結合された薬物、及び前記トリガー部分に関するアクチベータを含み、
前記トリガー部分は、ジエノフィルを含み、
前記アクチベータは、ジエンを含み、
前記ジエノフィルは、下記式(1a)を満たす:
キット。
(1)結合PQ、QP、QX、XQ、XZ、ZX、ZY、YZ、YA、AYの1つは、−CRaXD−CRaYD−から構成され、A、Y、Z、X、Q、Pによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDはO−C(O)−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)であり;かつYDはNHRc、OH、SHであり;又はXDはC(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;かつYDはCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2又はNH−OHである;
(2)AはCRaXDでありかつZはCRaYDである、又はZはCRaXDでありかつAはCRaYDである、又は、PはCRaXDでありかつXはCRaYDである、又はXはCRaXDでありかつPはCRaYDであり、XD及びYDは互いに関連してトランス型に配置され;A、Y、Z、X、Q、及びPによって構成される残基は、互いに独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDは、O−C(O)−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)であり、かつYDはNHRc、OH、SH、CRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2又はNH−OHである;又はXDはCRc 2−O−C(O)−(LD)n−(DD)、CRc 2−S−C(O)−(LD)n−(DD)、CRc 2−O−C(S)−(LD)n−(DD)、CRc 2−S−C(S)−(LD)n−(DD)、CRc 2−NRc−C(O)−(LD)n−(DD)、CRc 2−NRc−C(S)−(LD)n−(DD)であり、かつYDはNHRc、OH、SHである;又はXDはC(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;かつYDはCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2、NH−OHである;
(3)AはCRaYDであり、かつ、P、Q、X、Zの1つはCRaXDであり、又は、PはCRaYD であり、かつ、A、Y、Z、Xの1つはCRaXDである、又はYはCRaYD であり、かつX又はPはCRaXDである、又は、QはCRaYDであり、かつ、Z又はAはCRaXDである、又は、Z又はXのいずれかはCRaYDであり、かつ、A又はPはCRaXDであり、XD及びYDは互いに関連してトランス型に配置され;A、Y、Z、X、Q及びPによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びA はCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sを構成する群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し; XDは(O−C(O))p−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)であり、YDはCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2、NH−OHであり; pは0又は1である;
(4)PはCRaYDであり、かつ、YはCRaXDである、又はAはCRaYDであり、かつ、QはCRaXDである、又はQはCRaYDであり、かつ、AはCRaXDである、又はYはCRaYDであり、かつPはCRaXDであり、XD及びYDは、互いに関連してトランス型に配置され;A、Y、Z、X、Q及びPから構成される残基は、互いに独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し; XDは(O−C(O))p−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)であり;YDはNHRc、OH、SHであり;pは0又は1である;
(5)YはYDであり、かつ、PはCRaXDである、又はQはYDであり、かつ、AはCRaXDであり;A、Y、Z、X、Q及びPによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDは(O−C(O))p−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)、C(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;YDはNHであり; pは0又は1である;
(6)YはYDであり、かつ、P又はQはXDである、又は、QはYDであり、かつ、A又はYはXDであり;A、Y、Z、X、Q及びPによって構成される残基は、各々独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S、及びS−Sから構成される群から選択されて存在し、Siがもし存在する場合には、SiはCRa 2又はOに隣接し;XDはN−C(O)−(LD)n−(DD)、N−C(S)−(LD)n−(DD)であり;YDはNHであり;
ここで、各々のRaは、独立して、H、アルキル、アリール、OR’、SR’、S(=O)R’’’、S(=O)2R’’’、S(=O)2NR’R’’、Si−R’’’、Si−O−R’’’、OC(=O)R’’’、SC(=O)R’’’、OC(=S)R’’’、SC(=S)R’’’、F、Cl、Br、I、N3、SO2H、SO3H、SO4H、PO3H、PO4H、NO、NO2、CN、OCN、SCN、NCO、NCS、CF3、CF2−R’、NR’R”、C(=O)R’、C(=S)R’、C(=O)O−R’、C(=S)O−R’、C(=O)S−R’、C(=S)S−R’、C(=O)NR’R”、C(=S)NR’R’’、NR’C(=O)−R’’’、NR’C(=S)−R’’’、NR’C(=O)O−R’’’、NR’C(=S)O−R’’’、NR’C(=O)S−R’’’、NR’C(=S)S−R’’’、OC(=O)NR’−R’’’、SC(=O)NR’−R’’’、OC(=S)NR’−R’’’、SC(=S)NR’−R’’’、NR’C(=O)NR’’−R’’、NR’C(=S)NR’’−R’’、CR’NR’’から構成される群から選択され、各々のR’及び各々のR’’は、独立して、H、アリール又はアルキルであり、R’’’は、独立して、アリール又はアルキルであり;各々のRbは、独立して、H、アルキル、アリール、O−アルキル、O−アリール、OHから構成される群から選択され;各々のRcは、独立して、H、C1−6アルキル及びC1−6アリールから選択され; 2つ以上のRa,b,c部分は、結合して環を形成しても良く; 及び(LD)nは、好ましくはS、N、NH又はOを介してTRに結合された、n= 0又は1を有する任意のリンカーであり、ここで、これらS、N、NH又はO原子はリンカーの一部であり、直鎖状に及び/又は分枝状に配置された複数のユニットを構成しても良く;DDは、好ましくはS、N、NH又はOを介して結合された1つ以上の治療的部分又は薬物であり、ここでこれらS、N、NH又はO原子は、前記治療的部分の一部である)。 - A、P、Q、X、Y、及びZは、結合PQ、QP、QX、XQ、XZ、ZX、ZY、YZ、YA、AYの1つが−CRaXD−CRaYD−から構成されるように選択され、A,Y,Z,X,Q,Pによって構成される残基は、互いに独立して、CRa 2、S、O、SiRb 2であり、P及びAはCRa 2であり、原子の非隣接ペアは、O−O、O−S及びS−Sから構成される群から選択されて存在し、Siが存在する場合にはSiはCRa 2又はOに隣接し;XDはO−C(O)−(LD)n−(DD)、S−C(O)−(LD)n−(DD)、O−C(S)−(LD)n−(DD)、S−C(S)−(LD)n−(DD)、NRc−C(O)−(LD)n−(DD)、NRc−C(S)−(LD)n−(DD)であり;かつYDはNHRc、OH、SHである;又はXDがC(O)−(LD)n−(DD)、C(S)−(LD)n−(DD)であり;かつYDがCRc 2NHRc、CRc 2OH、CRc 2SH、NH−NH2、O−NH2又はNH−OHである、
請求項1に記載のキット。 - PQ、QP、AY又はYAが、−CRaXD−CRaYD−であり、XD及びYDが互いに関連してトランスに位置する、
請求項2に記載のキット。 - ZX又はXZが−CRaXD−CRaYD−であり、XD及びYDが互いに関連してシスに位置する、
請求項2に記載のキット。 - XDがNRc−C(O)−(LD)n−(DD)であり、YDがNHRcである、
請求項1乃至4のいずれか一項に記載のキット。 - 前記ジエノフィルが、次構造から選択される化合物である、
請求項5に記載のキット。
- 前記アクチベータは、式(2)−(4)に係る、前記ジエンから選択されるジエンを含む、請求項1乃至6のいずれか一項に記載のキット。
- 前記ジエンは、発明の詳細な説明で与えられるように、式(7)を満たし、R1及びR2でパラ置換されたテトラジエンである、
請求項7に記載のキット。
(ただし式中、R1及びR2は、各々独立して、H、アルキル、NO2、F、Cl、CF3、CN、COOR、CONHR、CONR2、COR、SO2R、SO2OR、SO2NR2、PO3R2、NO、2−ピリジル、3−ピリジル、4−ピリジル、2,6−ピリミジル、3,5−ピリミジル、2,4−ピリミジル、2,4イミダジル、2,5イミダジル及びフェニルから構成される群から選択される置換基であり、場合により、NO2、F、Cl、CF3、CN、COOR、CONHR、CONR、COR、SO2R、SO2OR、SO2NR2、PO3R2、NO及びArから構成される群から選択される1つ以上の電子求引性基で置換されており、ここで、RはH又はC1−C6アルキルであり、Arはフェニル、ピリジル又はナフチルである)。 - 前記ジエンは、
請求項7に記載のキット。 - 前記ジエンは、
請求項7に記載のキット。 - 前記薬物DD又は前記リンカーLD又は前記トリガー部分TRの少なくとも1つは、好ましくは抗体である、標的化試薬TTを含む、
請求項1乃至10のいずれか一項に記載のキット。 - 前記LD又は前記トリガー部分TRの少なくとも一方は、好ましくはペプチドである、マスキング部分MMを含む、
請求項1乃至10のいずれか一項に記載のキット。 - 前記薬物は、T−細胞係合抗体構成物である、
請求項1乃至12のいずれか一項に記載のキット。 - 前記プロドラッグは、抗体−トキシン又は抗体−薬物共役物を含む、
請求項1乃至11のいずれか一項に記載のキット。 - 請求項1乃至6のいずれか一項に記載の式(1a)のジエノフィル部分に、直接的に又は非直接的に結合された薬物化合物を含む、プロドラッグ。
- 薬物を供し、該薬物を請求項1乃至6のいずれか一項に記載の式(1a)のジエノフィル部分に化学的に結合させることを含む、非生物的、生体直交型反応によって引き起こされ得る、プロドラッグへと薬物化合物を変化させる方法。
- 治療方法であって、
薬物によって調節され得る疾患を患っている患者が、前記患者に、活性化後に前記薬物が放出されるトリガー部分を含むプロドラッグを投与することによって治療され、
前記トリガー部分は、トランス−シクロオクテン環を含み、該環は、場合によって、1つ以上のヘテロ原子を含み、前記ジエンは、逆電子要請型ディールスアルダー反応で、前記ジエノフィルと反応し得るように選択され、前記トリガー部分は、請求項1乃至6のいずれか一項に記載の式(1a)を満たす、
治療方法。 - 請求項1乃至6のいずれか一に記載の式(1a)を満たす化合物であって:
- 請求項1乃至6のいずれか一項に記載の式(1a)を満たす化合物に結合された物質の、生理的環境での、放出のためのアクチベータとしての、テトラジンの使用。
- 請求項1乃至6のいずれか一項に記載の式(1a)を満たす化合物と、化学的に結合された形態で投与された物質の、生理的環境での、放出のための化学的ツールとしてのテトラジンと、の間の逆電子要請型ディールスアルダー反応の使用であって、
前記物質は、式(1a)を満たす化合物に結合されている、
使用。 - 請求項1乃至6のいずれか一項に記載の式(1a)を満たし、治療用化合物のためのキャリアとしての、トランス−シクロオクテンの使用。
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