JP2013528596A - 網膜中および/または網膜下における液体貯留の処置のための方法および組成物 - Google Patents
網膜中および/または網膜下における液体貯留の処置のための方法および組成物 Download PDFInfo
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Abstract
Description
本発明は、網膜中および/または網膜下における液体貯留の処置のための方法および組成物を提供する。
イオンチャネルおよびアクアポリンは、網膜細胞においてディファレンシャルに発現しており、網膜の水分補給(hydration)を適切にコントロールするために極めて重大なイオンおよび水の移動に重要な役割を果たす。
本発明は、網膜中および/または網膜下における液体貯留を処置するための方法および組成物を提供する。
本発明者らは、in vitro網膜ミュラーグリア細胞(RMG)、ex vivoラット器官培養物およびin vivoラット網膜へのイオンチャネルおよびアクアポリンの発現調節に及ぼすMR活性化の直接的な役割を評価した。その結果は、アルドステロンが網膜でのアクアポリン1、4およびKir4.1の発現および/または分布をレギュレーションすることを示している。
− プレグン−4−エン−7,21−ジカルボン酸、9,11−エポキシ−17−ヒドロキシ−3−オキソ−、γ−ラクトン、メチルエステル、(7α,11α,17β)
− プレグン−4−エン−7,21−ジカルボン酸、9,11−エポキシ−17−ヒドロキシ−3−オキソ−、ジメチルエステル、(7α,11α,17β)
− 3’H−シクロプロパ[6,7]プレグナ−4,6−ジエン−21−カルボン酸、9,11−エポキシ−6,7−ジヒドロ−17−ヒドロキシ−3−オキソ−、γ−ラクトン、(6β,7β,11α,17β)
− プレグン−4−エン−7,21−ジカルボン酸、9,11−エポキシ−17−ヒドロキシ−3−オキソ−、7−(1−メチルエチル)エステル、一カリウム塩、(7α,11α,17β)
− プレグン−4−エン−7,21−ジカルボン酸、9,11−エポキシ−17−ヒドロキシ−3−オキソ−、7−メチルエチル)エステル、一カリウム塩、(7α,11α,17β)
− 3’H−シクロプロパ[6,7]プレグナ−1,4,6−トリエン−21−カルボン酸、9,11−エポキシ−6,7−ジヒドロ−17−ヒドロキシ−3−オキソ−、Γ−ラクトン(6β,7β,11α)
− 3’H−シクロプロパ[6,7]プレグナ−4,6−ジエン−21−カルボン酸、9,11−エポキシ−6,7−ジヒドロ−17−ヒドロキシ−3−オキソ−、メチルエステル、(6β,7β,11α,17β)
− 3’H−シクロプロパ[6,7]プレグナ−4,6−ジエン−21−カルボン酸、9,11−エポキシ−6,7−ジヒドロ−17−ヒドロキシ−3−オキソ−、一カリウム塩、(6β,7β,11α,17β)
− 3’H−シクロプロパ[6,7]プレグナ−1,4,6−トリエン−21−カルボン酸、9,11−エポキシ−6,7−ジヒドロ−17−ヒドロキシ−3−オキソ−、γ−ラクトン(6β,7β,11α,17β)
− プレグン−4−エン−7,21−ジカルボン酸、9,11−エポキシ−17−ヒドロキシ−3−オキソ−、γ−ラクトン、エチルエステル、(7α,11α,17β)
− プレグン−4−エン−7,21−ジカルボン酸、9,11−エポキシ−17−ヒドロキシ−3−オキソ−、γ−ラクトン、1−メチルエチルエステル(7α,11α,17β)
が含まれる。
によって定義されるスピロラクトン型化合物のファミリーが含まれ、上式で:
であり、
− Rは、炭素原子が最大5個の低級アルキルであり、
である。
− 7α−アセチルチオ−3−オキソ−4,15−アンドロスタジエン−[17(β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン;
− 3−オキソ−7α−プロピオニルチオ−4,15−アンドロスタジエン−[17((β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン;
− 6β,7β−メチレン−3−オキソ4,15−アンドロスタジエン−[17((β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン;
− 15α,16α−メチレン−3−オキソ−4,7α−プロピオニルチオ−4−アンドロステン[17(β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン;
− 6β,7β,15α,16α−ジメチレン−3−オキソ−4−アンドロステン[17(β−1’)−スピロ−5’]−ペルヒドロフラン−2’−オン;
− 7α−アセチルチオ−15β,16β−メチレン−3−オキソ−4−アンドロステン−[17(β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン;
− 15β,16β−メチレン−3−オキソ−7β−プロピオニルチオ−4−アンドロステン−[17(β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン;および
− 6β,7β,15β,16β−ジメチレン−3−オキソ−4−アンドロステン−[17(β−1’)−スピロ−5’]ペルヒドロフラン−2’−オン
である。
− 1α−アセチルチオ−15β,16β−メチレン−7α−メチルチオ−3−オキソ−17α−プレグン−4−エン−21,17−カルボラクトン;および
− 15β,16β−メチレン−1α,7α−ジメチルチオ−3−オキソ−17α−プレグン−4−エン−21,17−カルボラクトン
である。
[式中、Rは低級アルキルであり、その例には、メチル、エチル、プロピルおよびブチルの低級アルキル基が含まれる]で示される構造によって定義される。対象となる具体的な化合物には、以下:
− 3β,21−ジヒドロキシ−17α−プレグナ−5,15−ジエン−17−カルボン酸γ−ラクトン;
− 3β,21−ジヒドロキシ−17α−プレグナ−5,15−ジエン−17−カルボン酸γ−ラクトン3−アセテート;
− 3β,21−ジヒドロキシ−17α−プレグン−5−エン−17−カルボン酸γ−ラクトン;
− 3β,21−ジヒドロキシ−17α−プレグン−5−エン−17−カルボン酸γ−ラクトン3−アセテート;
− 21−ヒドロキシ−3−オキソ−17α−プレグン−4−エン−17−カルボン酸γ−ラクトン;
− 21−ヒドロキシ−3−オキソ−17α−プレグナ−4,6−ジエン−17−カルボン酸γ−ラクトン;
− 21−ヒドロキシ−3−オキソ−17α−プレグナ−1,4−ジエン−17−カルボン酸γ−ラクトン;
− 7α−アシルチオ−21−ヒドロキシ−3−オキソ−17α−プレグン−4−エン−17−カルボン酸γ−ラクトン;および
− 7α−アセチルチオ−21−ヒドロキシ−3−オキソ−17α−プレグン−4−エン−17−カルボン酸γ−ラクトン
が含まれる。
[式中、E’は、エチレン基、ビニレン基および(低級アルカノイル)チオエチレン基から成る群より選択され、E”は、エチレン基、ビニレン基、(低級アルカノイル)チオエチレン基および(低級アルカノイル)チオプロピレン基から成る群より選択され;E’およびE”がそれぞれエチレン基および(低級アルカノイル)チオエチレン基であるときにRが水素およびメチル基から成る群より選択される場合を除き、Rはメチル基であり;E’およびE”の選択は、少なくとも1個の(低級アルカノイル)チオ基が存在するように行われる]によって表される。
− 7α−アセチルチオ−17α−(2−カルボキシエチル)−17β−ヒドロキシ−アンドロスタ−4−エン−3−オンラクトン;
− 7β−アセチルチオ−17α−(2−カルボキシエチル)−17β−ヒドロキシ−アンドロスタ−4−エン−3−オンラクトン;
− 1α,7α−ジアセチルチオ−17α−(2−カルボキシエチル)−17β−ヒドロキシ−アンドロスタ−4,6−ジエン−3−オンラクトン;
− 7α−アセチルチオ−17αe−(2−カルボキシエチル)−17β−ヒドロキシ−アンドロスタ−1,4−ジエン−3−オンラクトン;
− 7α−アセチルチオ−17α−(2−カルボキシエチル)−17β−ヒドロキシ−19−ノルアンドロスタ−4−エン−3−オンラクトン;および
− 7α−アセチルチオ−17α−(2−カルボキシエチル)−17β−ヒドロキシ−6α−メチルアンドロスタ−4−エン−3−オンラクトン
が含まれる。
で示される基を包含する。
要約
グルココルチコイド(G)は糖尿病黄斑浮腫を軽減するが、Gの効果の根底をなすメカニズムの解明は不十分である。Gは、グルココルチコイド(GR)レセプターおよびミネラルコルチコイド(MR)レセプターに結合することができる。本発明者らは、MRの活性化が網膜の水分補給に影響しうるという仮説を立てている。培養網膜ミュラーグリア細胞(RMG、網膜の液体ホメオスタシスに寄与する)、ルイスラット網膜外植片、およびアルドステロンを注射された眼由来の網膜におけるイオン/水チャネルの発現に及ぼすMRアゴニストであるアルドステロンの効果(24時間)を検討した(リアルタイムPCR、ウエスタンブロット、免疫蛍光)。本発明者らは、MR、GRおよび11−βヒドロキシステロイドデヒドロゲナーゼII型の細胞特異的発現を証明した。アルドステロンは、MRおよびGRを占有することによりナトリウムチャネルENaC−α(6.5倍)およびカリウムチャネルKir4.1(1.9倍)の発現を有意に高め、その一方でアクアポリン4(AQP4、2.9倍)のアップレギュレーションはMR選択的である。アルドステロンの硝子体内注射は、網膜膨化(偽注射された眼よりも24%増加)およびRMGの活性化を誘導する。それは、RMGの頂端側微絨毛方向へのKir4.1およびAQP4の追加的な配置を促進する。本発明者らの結果は、神経網膜のミネラルコルチコイド感受性を際立たせ、アルドステロンがRMGでのイオンチャネル/水チャネル発現のレギュレーションにより健康な網膜の水分補給をコントロールすることを示している。これらの結果は、病的網膜における異常なMRシグナル伝達を将来的に研究するための理論的根拠を提供している。
イオンチャネルおよびアクアポリンは、網膜細胞においてディファレンシャルに発現され、網膜水分補給を適切にコントロールするために重大なイオンおよび水の移動において重要な役割を果たす。特に、網膜ミュラーグリア細胞(RMG)は、一方で網膜ニューロンと網膜血管の間の、他方で硝子体腔および網膜下腔との解剖学的で機能的な関係を確立することから、網膜の水分補給のコントロールおよびカリウムのホメオスタシスのための主要な要素である。網膜排水過程における任意の変化は、網膜浮腫につながる。
動物:全ての実験は、European Communities Council Directive 86/609/EECに準じて行われ、地域の倫理委員会によって承認された。成雌性ルイスラット(8〜12週齢、Janvier, Le Genest-Saint-Isle, France)をRMG初代培養物の調製、網膜器官培養物およびin vivo実験のために使用した。二酸化炭素の吸入によってラットを屠殺した。
MR、GRおよびHSD2は、網膜細胞において共発現される:アルドステロン依存性効果を調査するための必要条件として、ラット網膜におけるコルチコステロイドレセプターの発現を評価した(正常なラット網膜の準薄切片中に網膜の異なるゾーンを理解のために用意する)。本発明者らは、GRがいくつかの網膜ゾーンに発現し、MRも同じ網膜領域、すなわち神経節細胞(神経節細胞層、GCL)の核、ならびに双極細胞、アマクリン細胞、水平細胞およびRMG細胞を含む内顆粒層(INL)中の細胞の核に発現していることを見出した。RMG細胞の核は、主としてINLの中央部分に位置する。網膜MRの免疫組織化学検査の特異性を評価するために、MR抗体を腎臓切片に使用し、免疫ラベルが予想通り遠位ネフロンに限定されることを示した。MRプロテクター酵素HSD2はMRと類似の配置を有し、神経節細胞およびINLの細胞、ならびに陽性対照として提供された遠位ネフロンに存在した。免疫組織化学法は定量法ではないものの、網膜および腎臓集合管においてMRとHSD2のラベル強度が匹敵することから、腎臓と同様に眼におけるそれらの顕著な発現レベルがアルドステロン/MR特異的効果を完全に可能にするはずであることが示唆される。
アルドステロンおよびミネラルコルチコイドレセプターは、腎尿細管の遠位部における腎臓ナトリウム再吸収の重要なモデュレーターであって、心筋細胞、血管内皮細胞、角化細胞またはニューロンのような非上皮細胞を含むいくつかの非腎臓組織においても作用する。基礎をなすシグナル伝達経路が大きく未確定なままであるものの、腎外効果の際立った特徴は、過度のミネラルコルチコイド活性化と病態の間の関連にある。例えば、心不全におけるMR拮抗の有益効果に関する報告は、過度のMRシグナル伝達が心血管の損傷を引き起こすという考えを導いた。マウスにおける脳特異的なMRの過剰発現から推測されるように、ニューロンMRは、脳において不安のモデュレーションに関与し得る。最近になって、眼もMRを発現することが示され、網膜の血管病態へのその関与が、酸素誘導網膜症のラットモデルで示された。アルドステロン自体は、網膜血管新生を促進しないのに対し、MRの拮抗作用はこのモデルにおける炎症および酸化ストレスに関連する病的血管新生を軽減した。この報告は、網膜におけるMRの発現も実証した。本研究は、MRが神経節細胞および内顆粒層細胞に発現していることを確認している。MRの発現は、また、ラットRMGの初代培養物およびラット網膜外植片から見出された。加えて、本発明者らは、以前に決定されなかった網膜における細胞特異的なGR発現パターンを提供する。本発明者らは、MRがMRプロテクター酵素HSD2と共発現することでアルドステロン特異的なMR占有およびRMG細胞における効果を許すことも示している。レセプター後の選択性メカニズムに関連する、HSD2による大部分のグルココルチコイドの不活性化は、網膜における特異的アルドステロン作用のための条件を提供するはずである。
本発明者らは、いくつかの実験を行った。以下にその結果を示す:
− アルドステロンは、RMG細胞での水チャネルAQP4のmRNA発現をアップレギュレーションする;アルドステロンとMR特異的アンタゴニスト(RU26752)との同時投与は、その誘導を完全にブロッキングし、AQP4のアップレギュレーションがMRの占有により起こることを示している。
− トリアムシノロン(TA)は、AQP4の発現を減少させ、これは、アルドステロンと明らかに反対の効果であることから、MR特異的アンタゴニストの効果を模倣している。したがって、グルココルチコイドおよびMRアンタゴニストは、AQP4の発現に対して匹敵する効果を有し、これは、MRアンタゴニストの投与が、トリアムシノロン処置の際に観察された効果に匹敵する抗浮腫効果を網膜に提供することを示唆している。
− グルココルチコイドであるデキサメタゾン(Dex)は、MRの遺伝子発現を減少させ、これは、MRアンタゴニストの添加によって反転されない効果である。
中心性漿液性網脈絡膜症(CSCR)は、主に後極、より具体的には黄斑を襲う急性漿液性網膜剥離である。この疾患は、脈絡膜血管拡張から始まり、次に網膜色素上皮細胞(RPE)間結合装置の開放、次に網膜中および/または網膜下における液体貯留が続く。
まとめると、本発明者らの実験結果は、MRアンタゴニストの臨床効果と一緒に、MR活性化が網膜下液体貯留を誘導すること、およびMRアンタゴニストがCSRCまたはびまん性上皮症が原因の網膜下および/または網膜中の液体貯留を呈する患者の処置に有効であることを実証している。
Goto-Kakizaki(GK)ラットは、糖尿病網膜症のモデルとして使用されている。
眼内スピロノラクトンは、GK糖尿病ラットにおいて網膜浮腫を効率的に軽減し、外節の形成を高める。これらの変化は、ERGによって実証される網膜の機能改善と相関する。
様々な参考文献が、本出願を通して本発明が属する技術分野の現況を説明している。これらの参考文献の開示は、本明細書によって本開示への参照により組み入れられる。
Claims (13)
- 糖尿病網膜症、緑内障、虚血、近視、中心性漿液性網脈絡膜症、または滲出型加齢性黄斑変性に関連する網膜中および/または網膜下における液体貯留の処置に使用するためのミネラルコルチコイドレセプター(MR)アンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤。
- グルココルチコイド、および
MRアンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤
を含む、糖尿病網膜症、緑内障、虚血、近視、中心性漿液性網脈絡膜症、または滲出型加齢性黄斑変性に関連する網膜中および/または網膜下における液体貯留の処置に使用するための薬学的組成物。 - a)グルココルチコイド;および
b)MRアンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤
を含む、糖尿病網膜症、緑内障、虚血、近視、中心性漿液性網脈絡膜症、または滲出型加齢性黄斑変性に関連する網膜中および/または網膜下における液体貯留の処置に使用するためのキット。 - 眼送達のための、請求項1記載のミネラルコルチコイドレセプター(MR)アンタゴニスト、請求項2記載の薬学的組成物または請求項3記載のキット。
- ミネラルコルチコイドレセプター(MR)アンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤を含む点眼製剤。
- 薬学的組成物が点眼製剤である、請求項2記載の薬学的組成物。
- a)グルココルチコイドを含む点眼製剤;および
b)MRアンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤を含む点眼製剤
を含む、請求項3記載のキット。 - ミネラルコルチコイドレセプター(MR)アンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤を含む、生分解性眼用インプラント。
- グルココルチコイドをさらに含む、請求項8記載の生分解性眼用インプラント。
- 糖尿病網膜症、緑内障、虚血、近視、中心性漿液性網脈絡膜症、または滲出型加齢性黄斑変性に関連する網膜中および/または網膜下における液体貯留の処置時にグルココルチコイドによって誘導される副作用の予防に使用するためのMRアンタゴニストまたはミネラルコルチコイドレセプター遺伝子発現阻害剤。
- ぶどう膜炎または色素性網膜炎または網膜細胞毒性浮腫または神経毒性浮腫に関連する網膜中および/または網膜下における液体貯留の処置に使用するためのMRアゴニスト。
- MRアゴニストを含む生分解性眼用インプラント。
- MRアゴニストがアルドステロンまたはそのアナログである、請求項11記載のMRアゴニストまたは請求項12記載の生分解性眼用インプラント。
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JP2018535954A (ja) * | 2015-10-13 | 2018-12-06 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 脈絡膜血管新生の処置のための方法及び医薬組成物 |
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Publication number | Publication date |
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EP3238781B1 (en) | 2019-07-31 |
IL222482A0 (en) | 2012-12-31 |
EP2568986A1 (en) | 2013-03-20 |
JP2018039824A (ja) | 2018-03-15 |
CA2796307A1 (en) | 2011-11-17 |
EP3238781A1 (en) | 2017-11-01 |
JP6425785B2 (ja) | 2018-11-21 |
EP2977084B1 (en) | 2017-07-05 |
US9610294B2 (en) | 2017-04-04 |
US20150216879A1 (en) | 2015-08-06 |
JP6435283B2 (ja) | 2018-12-05 |
ES2641144T3 (es) | 2017-11-07 |
WO2011141456A1 (en) | 2011-11-17 |
JP2016138116A (ja) | 2016-08-04 |
EP2568986B1 (en) | 2016-01-13 |
ES2566934T3 (es) | 2016-04-18 |
US20130131024A1 (en) | 2013-05-23 |
EP2977084A1 (en) | 2016-01-27 |
US8957052B2 (en) | 2015-02-17 |
JP6148175B2 (ja) | 2017-06-14 |
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