JP2020528054A - サイトカインモジュレーション - Google Patents
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- JP2020528054A JP2020528054A JP2020502296A JP2020502296A JP2020528054A JP 2020528054 A JP2020528054 A JP 2020528054A JP 2020502296 A JP2020502296 A JP 2020502296A JP 2020502296 A JP2020502296 A JP 2020502296A JP 2020528054 A JP2020528054 A JP 2020528054A
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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Abstract
Description
本出願は、参照により本明細書に組み込まれる、0217年7月19日出願の米国仮特許出願第62/534,595号に対する優先権を主張する。
分野
本発明は、コネキシン43ヘミチャネルを含むコネキシンヘミチャネル、ならびにVEGF、IL−6、IL−8、MCP−1およびsICAM−1を含むサイトカインに、一般に関する。
本明細書で言及される全ての米国特許、米国特許出願公開公報、外国特許、外国およびPCTの公開された出願、論文ならびに他の文書、参考文献および刊行物、ならびに本明細書に由来する任意の特許(単数または複数)において引用された参考文献として列挙された全てのものは、それらの全体が参照により本明細書に組み込まれる。組み込まれた情報は、テキストおよび他の内容の全てが本出願において繰り返されるかのように事実上本出願の一部であり、出願時の本出願のテキストおよび内容の一部として扱われる。
以下は、本発明を理解する際に有用であり得る情報を含む。これは、本明細書で具体的または黙示的に言及される情報、刊行物または文書のいずれかが、本明細書で記載されるまたは特許請求される発明の先行技術であることの告白でも、本明細書で記載されるまたは特許請求される発明にとって必須であることの告白でもない。
ギャップジャンクションおよびヘミチャネルは、分子質量が最大で約1kDaの種々の小分子、例えば、イオン、小さい代謝物、cAMP、ATP、IP3、プロスタグランジンなどの移行に関与する。Burra S and Jiang JX, Regulation of cellular function by connexin hemichannels, Int J Biochem Mol Biol. 2(2): 119-128 (2011)。生理的条件下で、ほとんどのコネキシンは、原形質膜中でヘミチャネルを形成し、これらは、ギャップジャンクション形成の間にドッキングして細胞−細胞チャネルを形成するまで閉口される。いくつかの例外はあるが、コネキシンヘミチャネル電流は、強い脱分極または0.5mMより下への細胞外カルシウムの低減によって活性化される傾向がある。従って、内因性コネキシンヘミチャネルの活性は、正常な生理的条件下では顕著でない可能性がある。しかし、表面露出された場合、ドッキングされていないヘミチャネルは、細胞質ゾルと細胞外空間との間での分子の交換を媒介できることが報告されている。従って、ヘミチャネルは、デフォルトでは閉口されるが、それらの開口を誘導するいくつかの合図、例えば、細胞外Ca2+濃度における低下(Evans et al., The gap junction cellular internet: connexin hemichannels enter the signaling limelight. Biochem J 397(1): 1-14 (2006))または腸内病原体による感染(Puhar et al., A Shigella Effector Dampens Inflammation by Regulating Epithelial Release of Danger Signal ATP through Production of the Lipid Mediator PtdIns5P, Immunity 39(6): 1121- 1131 (2013);Tran Van Nhieu et al., Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells, Nat Cell Biol 5(8): 720-726 (2003))が記載されている。Puhar A and Sansonetti PJ, Dye-uptake Experiment through Connexin Hemichannels, Bio-protocol 4(17): e1221 (Sept. 2014)を参照のこと。ギャップジャンクション、ヘミチャネルおよびコネキシン調節因子は、種々の治療的使用のために提唱されてきた。
本明細書で記載され特許請求される発明は、この発明の概要に示されるまたは記載されるまたは言及されるものが含まれるがそれらに限定されない多くの性状および実施形態を有する。本発明は、包括的であることは意図しておらず、本明細書で記載され特許請求される発明は、限定ではなく例示のみを目的として含まれる、この導入部において同定された特色または実施形態に限定されることも、それらによって限定されることもない。
定義
「小分子」は、約600〜900ダルトン未満の分子量を有すると本明細書で定義され、一般に、有機化合物である。小分子は、ヘミチャネル遮断剤プロドラッグの活性薬剤であり得る。一実施形態では、小分子は、600ダルトン未満である。別の実施形態では、小分子は、900ダルトン未満である。
コネキシン
ヘミチャネル遮断剤
小分子ヘミチャネル遮断剤
Yは、C−R1であり;
R1は、アセチルであり;
R2は、水素、C3〜8シクロアルキル、必要に応じて酸素によって割り込まれたもしくはヒドロキシによって置換されているC1〜6アルキル、C1〜6アルコキシもしくは置換されているアミノカルボニル、C1〜6アルキルカルボニル、C1〜6アルコキシカルボニル、C1〜6アルキルカルボニルオキシ、C1〜6アルコキシ、ニトロ、シアノ、ハロ、トリフルオロメチルまたはCF3S;あるいは基CF3−A−(式中、Aは、−CF2−、−CO−、−CH2−、CH(OH)、SO2、SO、CH2−O−またはCONHである);あるいは基CF2H−A’−(式中、A’は、酸素、硫黄、SO、SO2、CF2またはCFHである);トリフルオロメトキシ、C1〜6アルキルスルフィニル、パーフルオロC2〜6アルキルスルホニル、C1〜6アルキルスルホニル、C1〜6アルコキシスルフィニル、C1〜6アルコキシスルホニル、アリール、ヘテロアリール、アリールカルボニル、ヘテロアリールカルボニル、ホスホノ、アリールカルボニルオキシ、ヘテロアリールカルボニルオキシ、アリールスルフィニル、ヘテロアリールスルフィニル、アリールスルホニルもしくはヘテロアリールスルホニル(ここで、任意の芳香族部分は、必要に応じて置換されている)、C1〜6アルキルカルボニルアミノ、C1〜6アルコキシカルボニルアミノ、C1〜6アルキル−チオカルボニル、C1〜6アルコキシ−チオカルボニル、C1〜6アルキル−チオカルボニルオキシ、1−メルカプトC2〜7アルキル、ホルミル、またはアミノスルフィニル、アミノスルホニルもしくはアミノカルボニル(ここで、任意のアミノ部分は、1つまたは2つのC1〜6アルキル基によって必要に応じて置換されている)、またはC1〜6アルキルスルフィニルアミノ、C1〜6アルキルスルホニルアミノ、C1〜6アルコキシスルフィニルアミノもしくはC1〜6アルコキシスルホニルアミノ、またはC1〜6アルキルカルボニル、ニトロもしくはシアノによって末端置換されているエチレニル、または−C(C1〜6アルキル)NOHもしくは−C(C1〜6アルキル)NNH2;あるいは1つもしくは2つのC1〜6アルキルによってまたはC2〜7アルカノイルによって必要に応じて置換されているアミノであり;R3およびR4の一方は、水素またはC1〜4アルキルであり、他方は、C1〜4アルキル、CF3またはCH2Xaであり、フルオロ、クロロ、ブロモ、ヨード、C1〜4アルコキシ、ヒドロキシ、C1〜4アルキルカルボニルオキシ、−S−C1〜4アルキル、ニトロ、1つもしくは2つのC1〜4アルキル基によって必要に応じて置換されているアミノ、シアノまたはC1〜4アルコキシカルボニルであるか;あるいはR3およびR4は一緒になって、C1〜4アルキルによって必要に応じて置換されているC2〜5ポリメチレンであり;
R5は、C1〜6アルキルカルボニルオキシ、ベンゾイルオキシ、ONO2、ベンジルオキシ、フェニルオキシもしくはC1〜6アルコキシであり、R6およびR9は水素であるか、またはR5はヒドロキシであり、R6は水素もしくはC1〜2アルキルであり、R9は水素であり;
R7は、ヘテロアリールまたはフェニルであり、これらは共に、クロロ、フルオロ、ブロモ、ヨード、ニトロ、C1〜4アルキルによって1度もしくは2度必要に応じて置換されているアミノ、シアノ、アジド、C1〜4アルコキシ、トリフルオロメトキシおよびトリフルオロメチルから選択される基または原子によって、1回または複数回が独立して必要に応じて置換されており;
R8は、水素、C1〜6アルキル、OR11またはNHCOR10であり、式中、R11は、水素、C1〜6アルキル、ホルミル、C1〜6アルカノイル、アロイルまたはアリール−C1〜6アルキルであり、R10は、水素、C1〜6アルキル、C1〜6アルコキシ、モノもしくはジC1〜6アルキルアミノ、アミノ、アミノ−C1〜6アルキル、ヒドロキシ−C1〜6アルキル、ハロ−C1〜6アルキル、C1〜6アシルオキシ−C1〜6アルキル、C1〜6アルコキシカルボニル−C1〜6−アルキル、アリールまたはヘテロアリールであり;R8−N−CO−R7基は、R5基に対してシスであり;Xは、酸素またはNR12であり、式中、R12は、水素またはC1〜6アルキルである]
を有する化合物の群から選択される。
ペプチドおよびペプチド模倣性ヘミチャネル遮断剤
コネキシン43(配列番号9)
他のコネキシンヘミチャネル遮断剤
ペプチド化学改変
化学構造改変
化学的送達改変
種々の方法が、ヘミチャネル遮断剤の活性または有効性を評価するために使用され得る。本発明の一態様では、対象におけるヘミチャネル遮断剤処置の効果は、サイトカインタンパク質アッセイを使用して評価またはモニタリングされる。サイトカインタンパク質レベルは、対象由来の試料中のタンパク質を検出および定量するのを可能にする任意の従来の方法によって定量され得る。非限定的な例示として、サイトカインタンパク質レベルは、例えば、サイトカイン結合能を有する抗体(または抗原決定基を含有するその断片)および形成された複合体の引き続く定量を使用することによって定量され得る。これらのアッセイにおいて使用される抗体は、標識されてもされなくてもよい。使用され得るマーカーの例示的な例には、放射性同位体、酵素、フルオロフォア、化学発光試薬、酵素基質または補因子、酵素阻害剤、粒子、色素などが含まれる。未標識の抗体(一次抗体)および標識された抗体(二次抗体)を使用する、本発明で使用され得る広範な公知のアッセイが存在する。これらの技術には、ウエスタンブロットまたはウエスタントランスファー、ELISA(酵素結合免疫吸着検定法)、RIA(ラジオイムノアッセイ)、競合的EIA(競合的酵素イムノアッセイ)、DAS−ELISA(二重抗体サンドイッチELISA)、免疫細胞化学的および免疫組織化学的技術、特異的抗体を含むタンパク質マイクロアレイもしくはバイオチップの使用に基づく技術、または尿試験紙などの形式のコロイド沈殿に基づくアッセイが含まれる。サイトカインを検出および定量するための他の方法には、親和性クロマトグラフィー技術、リガンド結合アッセイなどが含まれる。免疫学的方法が使用される場合、高い親和性でサイトカインタンパク質に結合することが公知の任意の抗体または試薬が、その量を検出するために使用され得る。それにもかかわらず、抗体、例えば、ポリクローナル血清、ハイブリドーマの上清またはモノクローナル抗体、抗体断片、Fv、Fab、Fab’およびF(ab’)2、scFv、ヒト化ディアボディ、トリアボディ、テトラボディ、ナノボディ、アルファボディ(alphabody)、ステープル(stapled)ペプチド、シクロペプチドならびに抗体の使用が好ましい。いくつかの営利会社によって提供される、本発明に関して使用され得る、市販の抗サイトカインタンパク質抗体が市場にある。
共投与
剤形および製剤ならびに投与
コネキシンヘミチャネル遮断剤と、サイトカイン阻害剤または他の薬剤との組合せ
コネキシンヘミチャネル遮断剤と、サイトカイン阻害剤または他の薬剤との組合せの製品/キット
用量、量および濃度
組合せ製品
製造および純度
(実施例1)
方法
(実施例2)
高グルコース+サイトカインの同時適用は、IL−6、sICAM−1、MCP−1、IL−8およびVEGF分泌を増加させた。
(実施例3)
コネキシンヘミチャネル遮断は、高グルコースとサイトカインの同時適用後にIL−6、IL−8、sICAM−1、MCP−1およびVEGFの発現を減少させる
(実施例4)
コネキシンヘミチャネル遮断は、高グルコース+サイトカインにより誘導されるATP放出を停止させる
(実施例5)
外因性細胞外ATPはIL−6、sICAM−1、MCP−1、IL−8またはVEGF放出を誘導しないが、IL−6、IL−8およびVEGF放出に対するコネキシンヘミチャネル遮断保護を逆転させる。
考察
引用文献
本出願は、参照により本明細書に組み込まれる、2017年7月19日出願の米国仮特許出願第62/534,595号に対する優先権を主張する。
配列表
本願は、ASCII形式で電子的に提出された配列表を含み、参照によってその全体が援用される。上記ASCIIのコピーは、2018年9月7日に作成され、名称がE3697−00506_SL.txtであり、サイズが55,553バイトである。
分野
本発明は、コネキシン43ヘミチャネルを含むコネキシンヘミチャネル、ならびにVEGF、IL−6、IL−8、MCP−1およびsICAM−1を含むサイトカインに、一般に関する。
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
対象においてサイトカイン活性をモジュレートするための方法であって、有効量のヘミチャネル遮断剤を前記対象に投与するステップを含む、方法。
(項目2)
前記サイトカインの存在または量が減少される、項目1に記載の方法。
(項目3)
前記サイトカインの存在または量における増加が阻害される、項目1に記載の方法。
(項目4)
前記サイトカインが、インターロイキン−6(IL−6)、インターロイキン−8(IL−8)、単球走化性タンパク質−1(MCP−1)および可溶性細胞内接着分子−1(sICAM−1)からなる群から選択される、項目1に記載の方法。
(項目5)
前記サイトカインが、血管内皮増殖因子である、項目1に記載の方法。
(項目6)
前記血管内皮増殖因子が、血管内皮増殖因子Aである、項目5に記載の方法。
(項目7)
前記ヘミチャネル遮断剤が、コネキシン43ヘミチャネル遮断剤である、項目1に記載の方法。
(項目8)
前記ヘミチャネル遮断剤が、小分子ヘミチャネル遮断剤である、項目1に記載の方法。
(項目9)
前記小分子ヘミチャネル遮断剤が、N−[(3S,4S)−6−アセチル−3−ヒドロキシ−2,2−ジメチル−3,4−ジヒドロクロメン−4−イル]−3−クロロ−4−フルオロベンズアミド(Xiflam)である、項目8に記載の方法。
(項目10)
前記ヘミチャネル遮断剤が、コネキシンペプチド模倣物である、項目1に記載の方法。
(項目11)
前記ヘミチャネル遮断剤が、VDCFLSRPTEKT(配列番号1)である、項目10に記載の方法。
(項目12)
前記ヘミチャネル遮断剤が、SRPTEKT(配列番号2)から本質的になる、項目10に記載の方法。
(項目13)
前記ヘミチャネル遮断剤が、ADCFLSRPTEKT(配列番号3)、VACFLSRPTEKT(配列番号4)、VDCFLSRPTAKT(配列番号5)、VDCFLSRPTEAT(配列番号6)、CFLSRPTEKT(配列番号7)、およびLSRPTEKT(配列番号8)から本質的になるペプチドからなる群から選択される、項目10に記載の方法。
(項目14)
VEGFアンタゴニストまたはVEGF受容体アンタゴニストを投与するステップをさらに含む、項目1に記載の方法。
(項目15)
前記VEGFが、VEGF−Aである、項目14に記載の方法。
(項目16)
IL−6アンタゴニストまたはIL−6受容体アンタゴニストを投与するステップをさらに含む、項目1に記載の方法。
(項目17)
IL−8アンタゴニスト、MCP−1アンタゴニストまたはsICAM−1アンタゴニストの1つまたは複数を投与するステップをさらに含む、項目1に記載の方法。
(項目18)
前記ヘミチャネル遮断剤が、コネキシン43ヘミチャネル遮断剤である、項目15に記載の方法。
(項目19)
血管新生が、低減または減弱される、項目18に記載の方法。
(項目20)
前記ヘミチャネル遮断剤が、注射によって投与される、項目1に記載の方法。
(項目21)
前記ヘミチャネル遮断剤が、経口投与される、項目1に記載の方法。
(項目22)
前記ヘミチャネル遮断剤が、PRNでもしくは所定のスケジュールで、またはその両方で投与される、項目1に記載の方法。
(項目23)
前記対象が、ヒトである、項目1に記載の方法。
(項目24)
前記ヘミチャネル遮断剤が、改変されたペプチド模倣物である、項目10に記載の方法。
(項目25)
前記改変が、C12−C12−VDCFLSRPTEKT(配列番号171)を含む、項目25に記載の方法。
(項目26)
前記対象が、病理学的な、異常な、不要な、または望ましくない量のサイトカイン活性を有する、項目1に記載の方法。
ペプチド化学改変
構造:C12−C12−Cxn43 MP(配列番号171)の構造。R1およびR2は、水素またはアルキル基であり得る。一部の態様では、R1=R2=n−ドデシル鎖。
化学的送達改変
Claims (26)
- 対象においてサイトカイン活性をモジュレートするための方法であって、有効量のヘミチャネル遮断剤を前記対象に投与するステップを含む、方法。
- 前記サイトカインの存在または量が減少される、請求項1に記載の方法。
- 前記サイトカインの存在または量における増加が阻害される、請求項1に記載の方法。
- 前記サイトカインが、インターロイキン−6(IL−6)、インターロイキン−8(IL−8)、単球走化性タンパク質−1(MCP−1)および可溶性細胞内接着分子−1(sICAM−1)からなる群から選択される、請求項1に記載の方法。
- 前記サイトカインが、血管内皮増殖因子である、請求項1に記載の方法。
- 前記血管内皮増殖因子が、血管内皮増殖因子Aである、請求項5に記載の方法。
- 前記ヘミチャネル遮断剤が、コネキシン43ヘミチャネル遮断剤である、請求項1に記載の方法。
- 前記ヘミチャネル遮断剤が、小分子ヘミチャネル遮断剤である、請求項1に記載の方法。
- 前記小分子ヘミチャネル遮断剤が、N−[(3S,4S)−6−アセチル−3−ヒドロキシ−2,2−ジメチル−3,4−ジヒドロクロメン−4−イル]−3−クロロ−4−フルオロベンズアミド(Xiflam)である、請求項8に記載の方法。
- 前記ヘミチャネル遮断剤が、コネキシンペプチド模倣物である、請求項1に記載の方法。
- 前記ヘミチャネル遮断剤が、VDCFLSRPTEKT(配列番号1)である、請求項10に記載の方法。
- 前記ヘミチャネル遮断剤が、SRPTEKT(配列番号2)から本質的になる、請求項10に記載の方法。
- 前記ヘミチャネル遮断剤が、ADCFLSRPTEKT(配列番号3)、VACFLSRPTEKT(配列番号4)、VDCFLSRPTAKT(配列番号5)、VDCFLSRPTEAT(配列番号6)、CFLSRPTEKT(配列番号7)、およびLSRPTEKT(配列番号8)から本質的になるペプチドからなる群から選択される、請求項10に記載の方法。
- VEGFアンタゴニストまたはVEGF受容体アンタゴニストを投与するステップをさらに含む、請求項1に記載の方法。
- 前記VEGFが、VEGF−Aである、請求項14に記載の方法。
- IL−6アンタゴニストまたはIL−6受容体アンタゴニストを投与するステップをさらに含む、請求項1に記載の方法。
- IL−8アンタゴニスト、MCP−1アンタゴニストまたはsICAM−1アンタゴニストの1つまたは複数を投与するステップをさらに含む、請求項1に記載の方法。
- 前記ヘミチャネル遮断剤が、コネキシン43ヘミチャネル遮断剤である、請求項15に記載の方法。
- 血管新生が、低減または減弱される、請求項18に記載の方法。
- 前記ヘミチャネル遮断剤が、注射によって投与される、請求項1に記載の方法。
- 前記ヘミチャネル遮断剤が、経口投与される、請求項1に記載の方法。
- 前記ヘミチャネル遮断剤が、PRNでもしくは所定のスケジュールで、またはその両方で投与される、請求項1に記載の方法。
- 前記対象が、ヒトである、請求項1に記載の方法。
- 前記ヘミチャネル遮断剤が、改変されたペプチド模倣物である、請求項10に記載の方法。
- 前記改変が、C12−C12−VDCFLSRPTEKT(配列番号171)を含む、請求項25に記載の方法。
- 前記対象が、病理学的な、異常な、不要な、または望ましくない量のサイトカイン活性を有する、請求項1に記載の方法。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014094917A (ja) * | 2012-11-09 | 2014-05-22 | Toyama Univ | インフラマソーム活性制御剤 |
WO2016029191A2 (en) * | 2014-08-22 | 2016-02-25 | Auckland Uniservices Limited | Channel modulators |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US4263428A (en) | 1978-03-24 | 1981-04-21 | The Regents Of The University Of California | Bis-anthracycline nucleic acid function inhibitors and improved method for administering the same |
DE3169595D1 (en) | 1980-11-10 | 1985-05-02 | Gersonde Klaus | Method of preparing lipid vesicles by ultrasonic treatment, the use of this method and apparatus for its application |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
US4485045A (en) | 1981-07-06 | 1984-11-27 | Research Corporation | Synthetic phosphatidyl cholines useful in forming liposomes |
DE3374837D1 (en) | 1982-02-17 | 1988-01-21 | Ciba Geigy Ag | Lipids in the aqueous phase |
DE3218121A1 (de) | 1982-05-14 | 1983-11-17 | Leskovar, Peter, Dr.-Ing., 8000 München | Arzneimittel zur tumorbehandlung |
EP0102324A3 (de) | 1982-07-29 | 1984-11-07 | Ciba-Geigy Ag | Lipide und Tenside in wässriger Phase |
US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
JPS607934A (ja) | 1983-06-29 | 1985-01-16 | Dai Ichi Seiyaku Co Ltd | リポソ−ムの製造方法 |
HUT35524A (en) | 1983-08-02 | 1985-07-29 | Hoechst Ag | Process for preparing pharmaceutical compositions containing regulatory /regulative/ peptides providing for the retarded release of the active substance |
EP0142641B1 (de) | 1983-09-26 | 1991-01-16 | Udo Dr. Ehrenfeld | Mittel und Erzeugnis für die Diagnose und Therapie von Tumoren sowie zur Behandlung von Schwächen der zelligen und humoralen Immunabwehr |
EP0143949B1 (en) | 1983-11-01 | 1988-10-12 | TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION | Pharmaceutical composition containing urokinase |
EP0673374B1 (en) | 1992-12-11 | 2000-03-01 | Smithkline Beecham Plc | Pharmaceutical composition containing bicyclic type compounds |
GB9702944D0 (en) * | 1997-02-13 | 1997-04-02 | Univ Manchester | Reducing fibrosis |
US7250397B2 (en) | 2000-02-23 | 2007-07-31 | Zealand Pharma A/S | Antiarrhythmic peptides |
EP1435925A2 (en) | 2001-10-17 | 2004-07-14 | University of Wales College of Medicine | Gap junctions and edhf |
EP1469875A1 (en) | 2002-01-29 | 2004-10-27 | Wyeth | Compositions and methods for modulating connexin hemichannels |
AU2005319155B2 (en) | 2004-12-21 | 2013-01-31 | Musc Foundation For Research Development | Compositions and methods for promoting wound healing and tissue regeneration |
WO2006134494A2 (en) * | 2005-02-03 | 2006-12-21 | Coda Therapeutics Limited | Anti-connexin compounds and therapeutic uses thereof |
JP4616237B2 (ja) | 2006-11-07 | 2011-01-19 | 日本電信電話株式会社 | シリコン化合物薄膜の形成方法 |
KR20100027091A (ko) * | 2006-11-15 | 2010-03-10 | 코다 테라퓨틱스, 인크. | 상처 치유를 위한 개선 방법 및 조성물 |
US20130281524A1 (en) | 2008-06-05 | 2013-10-24 | Peter Blower | Novel treatments |
GB201322934D0 (en) | 2013-12-23 | 2014-02-12 | Proximagen Ltd | Prodrug compounds |
GB201322932D0 (en) | 2013-12-23 | 2014-02-12 | Proximagen Ltd | Pro-drug compounds |
US20170056468A1 (en) * | 2014-02-25 | 2017-03-02 | Coda Therapeutics, Inc. | Treatment of resistant lesions |
-
2018
- 2018-07-19 CA CA3070089A patent/CA3070089A1/en active Pending
- 2018-07-19 WO PCT/US2018/042962 patent/WO2019018691A1/en unknown
- 2018-07-19 CN CN201880060106.7A patent/CN111372599A/zh active Pending
- 2018-07-19 US US16/040,412 patent/US11344603B2/en active Active
- 2018-07-19 EP EP18834756.1A patent/EP3655005A4/en active Pending
- 2018-07-19 JP JP2020502296A patent/JP2020528054A/ja active Pending
-
2022
- 2022-05-27 US US17/826,594 patent/US20220288163A1/en active Pending
-
2023
- 2023-09-19 JP JP2023151704A patent/JP2023166585A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014094917A (ja) * | 2012-11-09 | 2014-05-22 | Toyama Univ | インフラマソーム活性制御剤 |
WO2016029191A2 (en) * | 2014-08-22 | 2016-02-25 | Auckland Uniservices Limited | Channel modulators |
Non-Patent Citations (5)
Title |
---|
BARRIENTOS, S. ET AL: "Growth factors and cytokines in wound healing", WOUD REP REG, vol. 16, JPN6022033613, 2008, pages 585 - 601, ISSN: 0005060757 * |
BIOCHIM. BIOPHYS. ACTA BIOMEMBR., vol. 1860, no. 1, JPN6023019236, January 2018 (2018-01-01), pages 192 - 201, ISSN: 0005060759 * |
KIM, Y. ET AL: "Role of Hemichannels in CNS Inflammation and the Inflammasome Pathway", ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, vol. 104, JPN6022033615, 2016, pages 1 - 37, XP055786355, ISSN: 0005060758, DOI: 10.1016/bs.apcsb.2015.12.001 * |
OKAMOTO, M. ET AL: "Constitutively Active Inflammasome in Human Melanoma Cells Mediating Autoinflammation via Caspase-1", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 285, no. 9, JPN6022033611, 2010, pages 6477 - 6488, XP055210236, ISSN: 0005060756, DOI: 10.1074/jbc.M109.064907 * |
PHARMACOL. THER., vol. 180, JPN6023019235, December 2017 (2017-12-01), pages 144 - 160, ISSN: 0005060760 * |
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EP3655005A1 (en) | 2020-05-27 |
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WO2019018691A1 (en) | 2019-01-24 |
US11344603B2 (en) | 2022-05-31 |
US20190030122A1 (en) | 2019-01-31 |
CN111372599A (zh) | 2020-07-03 |
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