JP2015527409A - 筋ジストロフィーを治療する方法 - Google Patents
筋ジストロフィーを治療する方法 Download PDFInfo
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- JP2015527409A JP2015527409A JP2015531326A JP2015531326A JP2015527409A JP 2015527409 A JP2015527409 A JP 2015527409A JP 2015531326 A JP2015531326 A JP 2015531326A JP 2015531326 A JP2015531326 A JP 2015531326A JP 2015527409 A JP2015527409 A JP 2015527409A
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Abstract
Description
本出願は、2012年9月10日付で出願された米国仮出願第61/699,189号、2013年3月15日付で出願された出願の米国仮出願第61/798,479号、および2013年3月15日付で出願された出願の米国出願第13/842,781号からの優先権を主張するものであり、各出願はその全体を本明細書において参照により援用する。
本発明は、アメリカ国立衛生研究所により授与された助成金(R43 AR060030、R21 NS058429−01、およびR21 AR060769)の下に、政府援助によって成されたものである。政府は、本発明において、所定の権利を有する。
本明細書において、α7β1インテグリン発現調節因子、およびそれを用いて、例えば筋ジストロフィー等の、α7β1インテグリン発現障害に関連する症状を治療する方法を開示する。本開示は、米国仮特許出願第61/533,059号に開示された内容に関連し、その全体を参照により本明細書において援用する。さらに、本開示の各化合物は、米国仮特許出願第61/798,479号明細書の別紙I(表6)および別紙II(表7)において特定されたものとしてもよく、当該表に記載される特徴を有していてもよい。記載の各特徴は、本願発明の根底にある記述的課題の解決に貢献するものとみなされる。記載の各特徴として、例えば、筋ジストロフィーを有する患者を治療するのに適したα7β1インテグリン調節的活性、α7β1インテグリン発現の促進、被験体における筋傷害または損傷の防止または抑制、被験体における筋再生の促進または維持、およびその組み合わせ等が挙げられる。
から選択した式を有する薬剤で構成され、
式中、R1およびR2はそれぞれ独立して、C1−10アルキル、置換C1−10アルキル、C1−10アルコキシ、置換C1−10アルコキシ、アシル、アシルアミノ、アシルオキシ、アシルC1−10アルコキシ、アミノ、置換アミノ、アミノアシル、アミノカルボニルC1−10アルキル、アミノカルボニルアミノ、アミノジカルボニルアミノ、アミノカルボニルオキシ、アミノスルホニル、C6−15アリール、置換C6−15アリール、C6−15アリールオキシ、置換C6−15アリールオキシ、C6−15アリールチオ、置換C6−15アリールチオ、カルボキシル、カルボキシエステル、(カルボキシエステル)アミノ、(カルボキシエステル)オキシ、シアノ、C3−8シクロアルキル、置換C3−8シクロアルキル、(C3−8シクロアルキル)オキシ、置換(C3−8シクロアルキル)オキシ、(C3−8シクロアルキル)チオ、置換(C3−8シクロアルキル)チオ、ハロ、ヒドロキシル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C1−10ヘテロアリールオキシ、置換C1−10ヘテロアリールオキシ、C1−10ヘテロアリールチオ、置換C1−10ヘテロアリールチオ、C2−10ヘテロシクリル、C2−10置換ヘテロシクリル、C2−10ヘテロシクリルオキシ、置換C2−10ヘテロシクリルオキシ、C2−10ヘテロシクリルチオ、置換C2−10ヘテロシクリルチオ、イミノ、オキソ、スルホニル、スルホニルアミノ、チオール、C1−10アルキルチオ、および置換C1−10アルキルチオ、チオカルボニルから選択され;または
2つのR1置換基は、おのおのが結合する原子とともに、C6−15アリール、置換C6−15アリール、C3−8シクロアルキル、置換C3−8シクロアルキル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C2−10置換ヘテロシクリル、および置換したC2−10ヘテロシクリルオキシから選択される環を形成してもよく;
2つのR2置換基は、おのおのが結合する原子とともに、C6−15アリール、置換C6−15アリール、C3−8シクロアルキル、置換C3−8シクロアルキル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C2−10置換ヘテロシクリル、および置換したC2−10ヘテロシクリルオキシから選択される環を形成してもよく;
A、B、C、D、E、およびFはそれぞれ独立して、炭素、窒素、酸素、または硫黄から選択することができ;および
nはゼロ、1、2、3、4、または5とすることができ;または
これらの化合物の組み合わせであって、
前記α7β1インテグリン調節因子により、α7β1インテグリンの発現または活性を、治療前のα7β1インテグリンの発現または活性と比較して増加させることによって、筋ジストロフィーを有する被験体を治療することを特徴とする。特定の開示の実施形態は、表10、11、6、および/または7に記載の化合物のうち1つ以上に関する(表6については米国仮特許出願第61/796,476号明細書の別紙I、表7については米国仮特許出願第61/796,476号明細書の別紙II参照)。
本発明をより詳細に記載し、当業者が本発明を実施する際の手引きとなるよう、以下に用語および方法について説明する。単数形の用語、例えば、冠詞「a」、「an」、および「the」は、文脈から明らかにそうでないことが示されていない限り、複数のものについても言及するものである。同様に、単語「or(または)」とは、文脈から明らかにそうでないことが示されていない限り、「and(および)」を含むことも意図するものである。用語「comprises」は、「includes」を意味する。したがって、「AまたはBを含む(“comprising A or B,”)」は、「A、B、またはAおよびBを含む(“including A、B、or A およびB,”)」ということを意味するものであり、付加的な要素を排除するものではない。
上記の定義は、許容外の置換パターン(例えば、5つの異なる基で置換したメチル、5価の炭素等)を含むことを意図したものでないことは、当業者には理解されるであろう。そのような許容外の置換パターンは当業者により容易に識別される。
本明細書において開示した方法においてα1β7 調節因子として使用可能な化合物をここに開示する。特定の開示した実施形態において、化合物は筋ジストロフィーの治療において効果を有するものである。化合物は、小分子治療剤である。開示した特定の実施形態において、小分子治療剤は、含ヘテロ原子骨格を備える環式化合物である。他の開示の実施形態において、小分子治療剤は、全炭素骨格を備える環式化合物である。開したある実施形態において、含ヘテロ原子骨格を備える環式化合物は次式:
を有し、
式中、各R1はそれぞれ独立して、C1−10アルキル、置換C1−10アルキル、C1−10アルコキシ、置換C1−10アルコキシ、アシル、アシルアミノ、アシルオキシ、アシルC1−10アルキルオキシ、アミノ、置換アミノ、アミノアシル、アミノカルボニルC1−10アルキル、アミノカルボニルアミノ、アミノジカルボニルアミノ、アミノカルボニルオキシ、アミノスルホニル、C6−15アリール、置換C6−15アリール、C6−15アリールオキシ、置換C6−15アリールオキシ、C6−15アリールチオ、置換C6−15アリールチオ、カルボキシル、カルボキシエステル、(カルボキシエステル)アミノ、(カルボキシエステル)オキシ、シアノ、C3−8シクロアルキル、置換C3−8シクロアルキル、(C3−8シクロアルキル)オキシ、置換(C3−8シクロアルキル)オキシ、(C3−8シクロアルキル)チオ、置換(C3−8シクロアルキル)チオ、ヒドロキシル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C1−10ヘテロアリールオキシ、置換C1−10ヘテロアリールオキシ、C1−10ヘテロアリールチオ、置換C1−10ヘテロアリールチオ、C2−10ヘテロシクリル、C2−10置換ヘテロシクリル、C2−10ヘテロシクリルオキシ、置換C2−10ヘテロシクリルオキシ、C2−10ヘテロシクリルチオ、置換C2−10ヘテロシクリルチオ、イミノ、オキソ、スルホニル、スルホニルアミノ、チオール、C1−10アルキルチオ、および置換C1−10アルキルチオ、チオカルボニルから選択され;または
2つのR1置換基は、それぞれが結合する原子とともに、C6−15アリール、置換C6−15アリール、C3−8シクロアルキル、置換C3−8シクロアルキル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C2−10置換ヘテロシクリル、およびC2−10ヘテロシクリルオキシから選択される置換した 環を形成してもよく;
A、B、C、D、およびEはそれぞれ独立して、炭素、窒素、酸素、および硫黄から選択することができ;および
nは、ゼロ、1、2、3、4、または5とすることができる。
式2
を有し、
式中、各R2は、それぞれ独立して、C1−10アルキル、置換C1−10アルキル、C1−10アルコキシ、置換C1−10アルコキシ、アシル、アシルアミノ、アシルオキシ、アシルC1−10アルキルオキシ、アミノ、置換アミノ、アミノアシル、アミノカルボニルC1−10アルキル、アミノカルボニルアミノ、アミノジカルボニルアミノ、アミノカルボニルオキシ、アミノスルホニル、C6−15アリール、置換C6−15アリール、C6−15アリールオキシ、置換C6−15アリールオキシ、C6−15アリールチオ、置換C6−15アリールチオ、カルボキシル、カルボキシエステル、(カルボキシエステル)アミノ、(カルボキシエステル)オキシ、シアノ、C3−8シクロアルキル、置換C3−8シクロアルキル、(C3−8シクロアルキル)オキシ、置換(C3−8シクロアルキル)オキシ、(C3−8シクロアルキル)チオ、置換(C3−8シクロアルキル)チオ、ヒドロキシル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C1−10ヘテロアリールオキシ、置換C1−10ヘテロアリールオキシ、C1−10ヘテロアリールチオ、置換C1−10ヘテロアリールチオ、C2−10ヘテロシクリル、C2−10置換ヘテロシクリル、C2−10ヘテロシクリルオキシ、置換C2−10ヘテロシクリルオキシ、C2−10ヘテロシクリルチオ、置換C2−10ヘテロシクリルチオ、イミノ、オキソ、スルホニル、スルホニルアミノ、チオール、C1−10アルキルチオ、および置換C1−10アルキルチオ、チオカルボニルから選択され;または
2つのR2置換基は、それぞれが結合する原子とともに、C6−15アリール、置換C6−15アリール、C3−8シクロアルキル、置換C3−8シクロアルキル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C2−10置換ヘテロシクリル、およびC2−10ヘテロシクリルオキシから選択される置換基を有する環を形成してもよく;
A、B、C、D、E、およびFは、それぞれ独立して、炭素、窒素、酸素、および硫黄から選択することができ;および
nは、ゼロ、1、2、3、4、または5とすることができる。
式3
を有してもよく、
式中、R3およびR4は、独立して、ヒドロキシル、水素、C1−10アルキル、置換C1−10アルキル、カルボキシル、アシル、アミノアシル、アシルアミノ、アミノ、置換アミノ、C6−15アリール、置換C6−15アリール、およびC1−10アルコキシから選択することができ;R5は、アミノ、置換アミノ、オキソ、ヒドロキシル、C1−10アルコキシ、およびイミノから選択され;およびnはゼロ、1、2、3、4、または5とすることができる。当業者は、破線が、ある化合物においては存在しその他の化合物においては存在しない場合のある任意結合を示すものであることを理解されよう。
式12
式13
式14
式中、R2およびnは本明細書に記載したものであり、Zは炭素および窒素から選択することができ、Yは窒素および酸素から選択することができ、また、各Xはそれぞれ独立して窒素および炭素から選択することができる。当業者には、破線が可変結合を示すものであり、当該可変結合は、各可変結合が付着する原子の結合価(valency)に応じて存在してもしなくてもよいものであることが理解されよう。例えば、式11において示す可変結合が存在する場合、Xは一般的に炭素である。なぜなら、炭素原子は4結合を受け入れることができるからである。そのような化合物においては、Xを窒素とすることができるが、しかしながら、当業者には、窒素原子が孤立電子対を用いて第4の結合を受け入れるため、窒素原子が正に帯電するであろうことが理解されるであろう。
式16
式18
式19
式20
式21
式中、各Y1およびY2はそれぞれ独立して、酸素、硫黄、およびNRbから選択することができ、Rbは本明細書において開示したものであり;およびR6は、R1について提供された置換基から選択される。本明細書において開示した化合物のいずれかを、例えば医学的に許容される塩、N−オキシド、プロドラッグ、および/または溶媒和化合物等の代替化学的形態において用いることもできる。特定の開示した実施形態において、化合物は、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩、重硫酸塩、リン酸塩、酸性リン酸塩、イソニコチン酸塩、酢酸塩、乳酸塩、サリチル酸塩、クエン酸塩、酒石酸塩、アスコルビン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、グルコン酸塩、糖酸塩、蟻酸塩、安息香酸塩、グルタミン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、p−トルエンスルホン酸塩、およびその組み合わせ等の医学的に許容される塩であってもよい。例示的な化合物を以下の表1〜表6Aに示す。
i.筋ジストロフィーを治療する方法
α7β1インテグリンは、筋ジストロフィー患者における疾病進行の主要な修飾因子であることが分かっている。筋肉におけるα7インテグリンの発現増加によって、筋ジストロフィーのマウスモデルにおける筋疾患を軽減できる。筋細胞に基づく分析評価(assay)(以下の実施例1に記載)を用いて、発明者らは、筋肉中のα7β1インテグリン発現をアップレギュレートする分子として以下のものを特定した:ラミニン−111;バルプロ酸;シクロピロックス・エタノールアミン;デフェロキサミン;2,2−ジピリジル;5α−コレスタン−3β−オル−6−オン;化合物ID#1001;化合物ID#1002;化合物ID#1003;およびコレスタンのアナログ類(表9参照)。これらの知見に基づき、α7β1インテグリンの発現または活性を増加させることにより筋ジストロフィーを治療する方法を開示する。
また、被験体において筋再生、修復、または維持を促進する方法を開示する。いくつかの例では、本方法は、筋再生、修復、または維持を必要とする被験体に、α7β1インテグリン調節因子の有効量を投与することを含み、α7β1インテグリン調節因子として、シクロピロックス・エタノールアミン、デフェロキサミン、2,2−ジピリジル;5α−コレスタン−3β−オル−6−オン、化合物ID#1001、化合物ID#1002、化合物ID#1003、N032−0003、N066−0070、N069−0071、N069−0075、N064−0028、N066−0053、N069−0073、1080−0573、または、本明細書の、例えば、表10、表11、表6(米国仮特許出願第61/796,476号明細書の別紙I参照)、表7(米国仮特許出願第61/796,476号明細書の別紙II参照)、表13等に記載した化合物またはその組み合わせ等のいずれか1つが挙げられ、α7β1インテグリン調節因子は、α7β1インテグリン発現または活性を、治療前のα7β1インテグリン発現または活性と比べて増加させることにより、被験体における筋再生、修復、または維持を促進する。
被験体における筋損傷または傷害を予見的に防止または減少する方法も開示する。いくつかの実施形態において、本方法は、α7β1インテグリン調節因子の有効量を被験体に投与することを含み、α7β1インテグリン調節因子は、シクロピロックス・エタノールアミン、デフェロキサミン、2,2−ジピリジル;5α−コレスタン−3β−オル−6−オン、化合物ID#1001、化合物ID#1002、化合物ID#1003、N032−0003、N066−0070、N069−0071、N069−0075、N064−0028、N066−0053、N069−0073、1080−0573、または本明細書において記載した化合物、例えば表10、表11、表6(2013年3月15日に出願された米国仮特許出願第61/796,476号明細書の別紙I参照、参照によりその全体を本明細書に援用する)、表7(2013年3月15日に出願された米国仮特許出願第61/796,476号明細書の別紙II参照、参照によりその全体を本明細書に援用する)、表13に記載したもののうちのいずれか1つ、またはその組み合わせを含み、α7β1インテグリン調節因子は、α7β1インテグリンの発現または活性を未治療のα7β1インテグリン発現または活性と比較して増加させることにより、被験体における筋傷害または損傷を予見的に防止または抑制する。
本明細書では、α7β1インテグリンの発現を促進する方法も開示する。いくつかの例では、これらの方法は、細胞をインテグリン調節因子の有効量と接触させることを含み、α7β1インテグリン調節因子は、シクロピロックス・エタノールアミン、デフェロキサミン、2,2−ジピリジル;5α−コレスタン−3β−オル−6−オン、化合物ID#1001、化合物ID#1002、化合物ID#1003、N032−0003、N066−0070、N069−0071、N069−0075、N064−0028、N066−0053、N069−0073、1080−0573、または本明細書において規定した化合物、例えば、表10、表11、表6(米国仮特許出願第61/796,476号明細書の別紙I参照)、表7(米国仮特許出願第61/796,476号明細書の別紙II参照)、表13において規定した化合物のいずれか1つ、またはその組み合わせを含み、既治療の細胞におけるα7β1インテグリン発現を、未治療の細胞におけるα7β1インテグリン発現と比較して増加させることにより、α7β1インテグリン発現を増加する。いくつかの例では、細胞は、例えば骨格筋細胞等の筋細胞である。いくつかの例では、筋細胞は哺乳動物に存在し、前記細胞を薬剤に接触させることは、当該薬剤を当該哺乳動物に投与することを含む。
開示の方法のいずれについても、α7β1インテグリン調節因子の有効量とは、特定の経路および濃度で投与したときに所望の反応(例えば、筋ジストロフィーの治療、筋再生の促進、筋損傷または傷害の修復、維持、予防、減少、またはα7β1インテグリン発現の促進等)を誘発するものである。
開示のα7β1インテグリン調節因子を投与する方法は定型化した手順であり、熟練臨床医により決定することができる。開示のα7β1インテグリン調節因子またはその他の治療物質の投与は、通常、局所的、経鼻、静脈内、経口、頭蓋内、筋肉内、非経口、またはインプラントであるが、原則的には直腸、経膣での使用も可能である。開示のα7β1インテグリン調節因子は、これらの手法の組み合わせにより被験体に投与してもよい。
開示のα7β1インテグリン調節因子の1つ以上および/または付加的な治療剤は、特定の経路および/または濃度で投与して、所望の反応を生成する。いくつかの例において、所望の反応とは、治療した疾病、障害、または症状の少なくとも1つを減少、寛解、除去、防止、または抑制するのに有効量のことであり、経験的に決定することができる。本開示の種々の実施形態において、所望の反応とは、筋再生、筋力低下の減少または防止、筋維持の促進、筋損傷または傷害の減少または防止、筋ジストロフィーに関連する1つ以上の兆候または症状の減少または防止である。
特定の例において、筋ジストロフィーに関連する1つ以上の兆候または症状を減少または抑制する薬剤の有効量投与の前に、最中に、または後に、被験体は1つ以上のその他の治療を受けることができる。一例において、被験体は、開示のα7β1調節因子の投与の前に、1つ以上の治療を受ける。そのような治療の例としては、限定はしないが、筋鞘を安定させ筋変性を減少する働きをする、ラミニン−111タンパク質療法がある。いくつかの例において、筋細胞源を添加して、筋再生および修復を支援することができる。本開示のいくつかの態様において、ラミニン療法と組み合わせて、被験体にサテライト細胞を投与する。本明細書において、本開示と矛盾しない限りにおいて援用により参照する米国特許公開第2006/0014287号は、筋芽細胞における細胞の集合体を濃縮して、それらの細胞を被験体に投与する方法を提供する。さらなる態様において、脂肪組織由来幹細胞等の幹細胞を被験体に投与する。脂肪組織由来幹細胞を調合および投与する好適な方法は、本開示と矛盾しない限りにおいて援用により参照する米国特許明細書第2007/0025972号において記載される。いくつかの例において、線維芽細胞等、その他の細胞形質成分(cellular material)を投与するともできる。
筋疾患の治療における開示のα7β1調節因子の1つ以上の使用について規制当局の認可を得るため、臨床試験を行った。当該技術分野において知られているように、臨床試験はいくつかの試験段階を経て進み、それぞれの段階を第I相、第II相、第III相、および第IV相とよぶ。
参加者の適格基準は、一般的なもの(例えば、年齢、性別、病型等)から特定的なもの(例えば、前治療の種類および回数、疾病特性、血球数、臓器機能)にまで及ぶ。一実施形態において、適正患者は筋障害を診断されている。適正基準は、試験段階によっても異なる場合がある。臨床試験の適格患者は、筋障害の主観的な測定および筋障害治療への非反応性に基づいて選択することもできる。例えば、第I相および第II相試験において、実験的治療に対し、臓器機能障害またはその他の要因を原因とするリスクがありうる患者は、これらの基準から除外されることが多い。第II相および第III相試験では、疾病の種類および段階および前治療の回数および種類に関して付加的な基準が含まれることが多い。
試験を始める前に、本技術分野で知られているいくつかの手段を用いてまず患者を分類することができる。患者の評価は、まず、血清クレアチンキナーゼ(CK)レベル、または、筋障害のその他の指標、例えば、筋肉の炎症、アポトーシス、筋消失、筋管肥大、および/または筋線維の安定性の減少および細胞寿命等を測定することにより、行うことができる。
開示のα7β1調節因子は、試験参加者に経口投与することが一般的である。薬剤の用量の範囲を試験することができる。前臨床試験からの情報を得れば、熟練の専門家は臨床試験における薬剤の適正な投与量をすぐに判定することができる。一実施形態において、用量の範囲は、被験体の体重の約100μg/kg〜約5000mg/kg、例えば、被験体の体重の1mg/kg〜約2000mg/kg、被験体の体重の約100mg/kg〜約1500mg/kg、被験体の体重の約100μg/kg〜約2000mg/kg、被験体の体重の約200mg/kg〜約1000mg/kg、被験体の体重の約200mg/kg〜約750mg/kg、被験体の体重の約250mg/kg〜約500mg/kg、約100μm〜約500mMである。いくつかの実施形態において、被験体には、1日当たり体重1キロ当たり10〜60mgの開示のα7β1調節因子を経口で与える。例えば、開示のα7β1調節因子を2週間にわたり10〜15mg/kg投与し、耐性がよければ、用量を5〜10mg/kg/週に増やして最適な臨床反応を達成する。いくつかの例では、1日容量は体重の60mg/kg以内とし、肝機能を2週間から1カ月ごとに監視しつつ最低6カ月投与する。
第I相基準を満たすため、開示のα7β1調節因子の分布を、例えば、定期的に採取した血液等の試料の化学的分析により監視する。例えば、治療開始後は、約72時間まで試料を定期的に採取することができる。
臨床試験のエンドポイントは、評価の段階で化合物の有効性を示す測定可能な成果である。試験を始める前にエンドポイントを設定し、臨床試験の種類および段階により変化することになるものである。エンドポイントの例としては、例えば、血清CKレベル、炎症、アポトーシス、および筋消失の減少等が挙げられる。例えば、血清レベルにおける10%の減少は、治療に対する患者の感受性を示す。
[実施例]
本実施例において、α7βgal+/−筋細胞中のLacZリポーター遺伝子がα7インテグリンプロモーターの転写活性を忠実に伝えることを示し、α7β1エンハンサー分子のスクリーニングに使用可能であることを示す。
本実施例において、α7β1インテグリン発現エンハンサーとして特定した複数の化合物について説明する。
本実施例は、ラミニン−111を筋肉内注射することによりmdxマウス中の筋ジストロフィーが防止されることを実証するものである。本実施例では、特にラミニン111についての研究について記載したが、本明細書において記載した方法および表8に示す特定のα7β1インテグリンエンハンサー分子の最適濃度に基づいて、その他のα7β1インテグリンエンハンサー分子について同様の研究を行いうることが考えられ、筋ジストロフィーについての同様の結果が得られることが予想される。
本実施例では、筋ジストロフィーの治療に利用可能なバルプロ酸の能力を示す研究について説明する。
本実施例では、シクロピロックス、2,2−ジピリジル、およびデフェロキサミンが、一般的な経路を介してα7インテグリン発現を増加することを説明する。
本実施例では、筋芽細胞および筋管中のα7インテグリン発現を増加する、コレスタンおよび特定のコレスタンアナログの機能について実証する。
筋細胞に基づく分析を用いて、(実施例2に記載したように)化合物のDIVERSetライブラリーをスクリーニングし、1001、1002、および1003とした3つの化合物はすべて、筋肉中におけるα7インテグリン発現を増加させた。化合物番号1001、1002、および1003は、ケムブリッジ社(ChemBridge Corporation)(サンディエゴ、カリフォルニア州)から市販されている。化合物番号1001は、3−メチル−2−[(2−オキソ−2−フェニルエチル)チオ]−3H−スピロ[ベンゾ[h]キナゾリン−5,1''−シクロペンタン]−4(6H)−オン(MW=417)である。化合物番号1002は、1−{2−[3−(4−メチル−1−ピペラジニル)プロポキシ]フェニル}−1−プロパノン塩酸塩(MW=327)である。化合物番号1003は、1{2−[3−(1−ピペルジニル)プロポキシ}フェニル}−1−プロパノン塩酸塩(MW=312)である。
本実施例において記載した研究は、mdxおよびdyWマウスにおいてα7インテグリンレベルを増加し疾病の症状を寛解させるLAM−111の有効性を実証するものである。本データを提供して、α7インテグリンを体内で促進すること、および筋ジストロフィーの治療に役立つものとすることが可能であることを実証する。よって、開示のα7β1エンハンサーはいずれもLAM−111と同様の生体内影響を有すると考えられ、したがって、筋ジストロフィーの治療剤として有用である。
本実施例では、筋肉中のα7インテグリン発現を増加させるための付加的な化合物についての構造(以下の表11)、例示的な合成反応(図29A〜図29H)、およびキャラクタリゼーション研究(図21〜図28参照)を提供する。いくつかの例において、各アナログは重さ5mg、塩形態(例えば、塩酸塩)、乾燥粉末として、HPLCによる測定において少なくとも90%の純度で作成する。その他の例示的な化合物を以下の表10に示す。本開示の化合物の特定の実施形態に対して行ったスクリーニングの結果を図32に示す。
Claims (42)
- 筋ジストロフィーを有する被験体を治療する方法であって、
α7β1インテグリン調節因子の有効量を、筋ジストロフィーを有する被験体に投与することを含み、
前記α7β1インテグリン調節因子は、シクロピロックス・エタノールアミン、デフェロキサミン、2,2−ジピリジル;5α−コレスタン−3β−オル−6−オン、N032−0003、N066−0070、N069−0071、N069−0075、N064−0028、N066−0053、N069−0073、1080−0573、および以下の式、すなわち、
から選択した式を有する薬剤で構成され、
式中、R1およびR2はそれぞれ独立して、C1−10アルキル、置換C1−10アルキル、C1−10アルコキシ、置換C1−10アルコキシ、アシル、アシルアミノ、アシルオキシ、アシルC1−10アルコキシ、アミノ、置換アミノ、アミノアシル、アミノカルボニルC1−10アルキル、アミノカルボニルアミノ、アミノジカルボニルアミノ、アミノカルボニルオキシ、アミノスルホニル、C6−15アリール、置換C6−15アリール、C6−15アリールオキシ、置換C6−15アリールオキシ、C6−15アリールチオ、置換C6−15アリールチオ、カルボキシル、カルボキシエステル、(カルボキシエステル)アミノ、(カルボキシエステル)オキシ、シアノ、C3−8シクロアルキル、置換C3−8シクロアルキル、(C3−8シクロアルキル)オキシ、置換(C3−8シクロアルキル)オキシ、(C3−8シクロアルキル)チオ、置換(C3−8シクロアルキル)チオ、ハロ、ヒドロキシル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C1−10ヘテロアリールオキシ、置換C1−10ヘテロアリールオキシ、C1−10ヘテロアリールチオ、置換C1−10ヘテロアリールチオ、C2−10ヘテロシクリル、C2−10置換ヘテロシクリル、C2−10ヘテロシクリルオキシ、置換C2−10ヘテロシクリルオキシ、C2−10ヘテロシクリルチオ、置換C2−10ヘテロシクリルチオ、イミノ、オキソ、スルホニル、スルホニルアミノ、チオール、C1−10アルキルチオ、置換C1−10アルキルチオ、またはチオカルボニルから選択され;または
2つのR1置換基は、おのおのが結合する原子とともに、C6−15アリール、置換C6−15アリール、C3−8シクロアルキル、置換C3−8シクロアルキル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C2−10置換ヘテロシクリル、または置換した C2−10ヘテロシクリルオキシから選択される環を形成してもよく;
2つのR2置換基は、おのおのが結合する原子とともに、C6−15アリール、置換C6−15アリール、C3−8シクロアルキル、置換C3−8シクロアルキル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C2−10置換ヘテロシクリル、または置換したC2−10ヘテロシクリルオキシから選択される環を形成してもよく;
A、B、C、D、E、およびFはそれぞれ独立して、炭素、窒素、酸素、または硫黄から選択することができ;および
nはゼロ、1、2、3、4、または5とすることができ;または
これらの化合物の組み合わせであって、
前記α7β1インテグリン調節因子により、α7β1インテグリンの発現または活性を、治療前のα7β1インテグリンの発現または活性と比較して増加させることによって、筋ジストロフィーを有する被験体を治療することを特徴とする、方法。 - 前記α7β1インテグリン調節因子は、化合物#1001、化合物#1002、化合物#1003、すなわち、
- 前記α7β1インテグリン調節因子は、以下の式、すなわち
式中、Y1は、酸素、硫黄、またはNRbから選択することができ、ここで、Rbは、水素、アルキル、置換アルキル、アリール、置換アリール、シクロアルキル、置換シクロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロシクリル、または置換ヘテロシクリルから選択することができ;および
R6は、C1−10アルキル、置換C1−10アルキル、C1−10アルコキシ、置換C1−10アルコキシ、アシル、アシルアミノ、アシルオキシ、アシルC1−10アルキルオキシ、アミノ、置換アミノ、アミノアシル、アミノカルボニルC1−10アルキル、アミノカルボニルアミノ、アミノジカルボニルアミノ、アミノカルボニルオキシ、アミノスルホニル、C6−15アリール、置換C6−15アリール、C6−15アリールオキシ、置換C6−15アリールオキシ、C6−15アリールチオ、置換C6−15アリールチオ、カルボキシル、カルボキシエステル、(カルボキシエステル)アミノ、(カルボキシエステル)オキシ、シアノ、C3−8シクロアルキル、置換C3−8シクロアルキル、(C3−8シクロアルキル)オキシ、置換(C3−8シクロアルキル)オキシ、(C3−8シクロアルキル)チオ、置換(C3−8シクロアルキル)チオ、ハロ、ヒドロキシル、C1−10ヘテロアリール、置換C1−10ヘテロアリール、C1−10ヘテロアリールオキシ、置換C1−10ヘテロアリールオキシ、C1−10ヘテロアリールチオ、置換C1−10ヘテロアリールチオ、C2−10ヘテロシクリル、C2−10置換ヘテロシクリル、C2−10ヘテロシクリルオキシ、置換C2−10ヘテロシクリルオキシ、C2−10ヘテロシクリルチオ、置換C2−10ヘテロシクリルチオ、イミノ、オキソ、スルホニル、スルホニルアミノ、チオール、C1−10アルキルチオ、置換C1−10アルキルチオ、またはチオカルボニルから選択される、請求項1に記載の方法。 - 前記α7β1インテグリン調節因子は、次式:
式中:
R1は、C(O)NH2、C(O)N[(CH2)0−5CH3]2、C(O)OH、C(O)OP(O)(OH)2、C(O)OC(O)C(CH3)3、C(O)OC(O)NMe2、またはC(O)O(CH2)0−5CH3から選択され;
R1’は、NH2またはN[(CH2)0−5CH3]2から選択され;
R2は、N[(CH2)0−5CH3]2から選択され;および
Y1は、酸素、硫黄、NH、N(CH2)0−5CH3、およびNCH2OP(O)(OH)2から選択される、請求項1に記載の方法。 - 前記α7β1インテグリン調節因子は、
- 前記α7β1インテグリン調節因子は、次式:
式中:
R1は、C(O)NH(Ph)pCH2NHC(O)Ot−Bu、C(O)N[CH2OP(O)(OH)2](Ph)pCH2NHC(O)Ot−Bu、C(O)N[CH2OP(O)(OH)2](Ph)pCH2N[CH2OP(O)(OH)2]C(O)Ot−Bu、C(O)NH(Ph)pCH2N[CH2OP(O)(OH)2]C(O)Ot−Bu、C(O)NH(Ph)pCH2NHC(O)OH、C(O)N[CH2OP(O)(OH)2](Ph)pCH2NHC(O)OH、C(O)NH(Ph)pCH2NHC(O)OMe、C(O)N[CH2OP(O)(OH)2](Ph)pCH2NHC(O)OMe、C(O)N[CH2OP(O)(OH)2](Ph)pCH2N[CH2OP(O)(OH)2]C(O)OMe、C(O)N[(CH2)0−5CH3](Ph)pCH2NHC(O)Ot−Bu、C(O)N[(CH2)0−5CH3](Ph)pCH2N[CH2OP(O)(OH)2]C(O)Ot−Bu、C(O)N[(CH2)0−5CH3](Ph)pCH2NHC(O)OH、C(O)N[(CH2)0−5CH3](Ph)pCH2N[CH2OP(O)(OH)2]C(O)OH、C(O)N[(CH2)0−5CH3](Ph)pCH2NHC(O)OMe、C(O)N[(CH2)0−5CH3](Ph)pCH2N[CH2OP(O)(OH)2]C(O)OMe、C(O)NH(Ph)pCH2NH2、C(O)N[CH2OP(O)(OH)2](Ph)pCH2NH2、C(O)NH(Ph)pCH2OH、C(O)N[CH2OP(O)(OH)2](Ph)pCH2OH、C(O)NH(Ph)pCH2N[(CH2)0−5CH3]2、C(O)N[CH2OP(O)(OH)2](Ph)pCH2N[(CH2)0−5CH3]2、C(O)NH(Ph)pCH2OMe、C(O)N[CH2OP(O)(OH)2](Ph)pCH2OMe、C(O)NH(Ph)pCH2SH、C(O)N[CH2OP(O)(OH)2](Ph)pCH2SH、C(O)NH(Ph)pCH2SMe、C(O)N[CH2OP(O)(OH)2](Ph)pCH2SMe、C(O)N[(CH2)0−5CH3](Ph)pCH2NH2、C(O)N[CH2OP(O)(OH)2](Ph)pCH2NH2、C(O)N[(CH2)0−5CH3](Ph)pCH2OH、C(O)N[CH2OP(O)(OH)2](Ph)pCH2OH、C(O)N[(CH2)0−5CH3](Ph)pCH2N[(CH2)0−5CH3]2、C(O)N[CH2OP(O)(OH)2](Ph)pCH2N[(CH2)0−5CH3]2、C(O)N[(CH2)0−5CH3](Ph)pCH2OMe、C(O)N[CH2OP(O)(OH)2](Ph)pCH2OMe、C(O)N[(CH2)0−5CH3](Ph)pCH2SH、C(O)N[CH2OP(O)(OH)2](Ph)pCH2SH、C(O)N[(CH2)0−5CH3](Ph)pCH2SMe、またはC(O)N[CH2OP(O)(OH)2](Ph)pCH2SMeから選択され;
R2は、(CH2)0−5CH3から選択され;および
Y1は、酸素、硫黄、NH、N(CH2)0−5CH3、またはNCH2OP(O)(OH)2から選択される、請求項1に記載の方法。 - 前記α7β1インテグリン調節因子は、
- 前記α7β1インテグリン調節因子は、次式:
式中:
R1は、水素、C(O)−Ph−p−Br、C(O)−Ph−p−Cl、C(O)−Ph−p−F、C(O)−Ph−p−I、C(O)−Ph−p−CF3、C(O)−Ph−m−Br、C(O)−Ph−m−Cl、C(O)−Ph−m−F、C(O)−Ph−m−I、C(O)−Ph−m−CF3、C(O)−Ph−o−Br、C(O)−Ph−o−Cl、C(O)−Ph−o−F、C(O)−Ph−o−I、C(O)−Ph−o−CF3、または(CH2)0−5CH3から選択され;および
R6は、N[CH2OP(O)(OH)2]C(O)−3−ブロモ−5−ピリジル、NHC(O)−3−ブロモ−5−ピリジル、N[(CH2)0−5CH3]C(O)−3−ブロモ−5−ピリジル、N[(CH2)0−5CH3]C(O)−3−フルオロ−5−ピリジル、N[CH2OP(O)(OH)2]C(O)−3−フルオロ−5−ピリジル、またはNHC(O)−3−フルオロ−5−ピリジルから選択される、請求項1に記載の方法。 - 前記α7β1インテグリン調節因子は、
- 前記α7β1インテグリン調節因子は、次式:
式中:
R1は、水素および(CH2)0−5CH3から選択され;
R2は、OMe、SH、SMe、NH2、N[(CH2)0−5CH3]2、OH、OP(O)(OH)2、OC(O)C(CH3)3、またはOC(O)NMe2から選択され;
R2’は、NO2であり;および
任意の環Aは、もし存在する場合は、フェニルである、請求項1に記載の方法。 - 前記α7β1インテグリン調節因子は、
- 前記α7β1インテグリン調節因子は、次式:
式中:
R1は、O(CH2)0−5CH3、OH、OP(O)(OH)2、OC(O)C(CH3)3、OC(O)NMe2、S(CH2)0−5CH3、SH、NH2、N[(CH2)0−5CH3]2、OCF3、またはCF3から選択され;
Y1は、NH、O、NCH2OP(O)(OH)2、またはSから選択され;および
Y2は、NH、O、NCH2OP(O)(OH)2、またはSから選択される、請求項1に記載の方法。 - 前記α7β1インテグリン調節因子は、
である、請求項12に記載の方法。 - 前記α7β1インテグリン調節因子は、269番1の1つ以上の化合物から選択される、請求項1に記載の方法。
- 前記α7β1インテグリン調節因子は、
- 前記筋ジストロフィーは、メロシン欠損型先天性1A型(MDC1A)、メロシン欠損型先天性筋ジストロフィー1D型(MDC1D)、肢体型筋ジストロフィー(LGMD)、デュシェンヌ型筋ジストロフィー(DMD)、福山型先天性筋ジストロフィー(FCMD)または顔面肩甲上腕型筋ジストロフィー(FHMD)である、請求項1に記載の方法。
- 前記筋ジストロフィーは、DMD、MDC1A、またはFCMDである、請求項16に記載の方法。
- 前記筋ジストロフィーはDMDである、請求項16に記載の方法。
- 前記α7β1インテグリン調節因子は付加的な治療剤とともに投与される、請求項1に記載の方法。
- 前記付加的な治療剤は、コスタメリックタンパク質、成長因子、サテライト細胞、幹細胞、ミオサイト、または付加的なα7β1インテグリン調節因子である、請求項19に記載の方法。
- 前記付加的なα7β1インテグリン調節因子は、ラミニン−111、ラミニン−111フラグメント、バルプロ酸、またはバルプロ酸アナログである、請求項20に記載の方法。
- 筋ジストロフィーを有する被験体を選択することをさらに含む、請求項1の方法。
- 前記筋ジストロフィーを有する被験体を選択することは、前記α7β1インテグリン調節因子の有効量を被験体に投与する前に筋ジストロフィーを有する被験体を診断することを含む、請求項22に記載の方法。
- 被験体において筋の再生、修復、または維持を促進する方法であって、
α7β1インテグリン調節因子の有効量を、筋の再生、修復、または維持を必要とする患者に投与することを含み、
前記α7β1インテグリン調節因子は、請求項1〜15のいずれか一項に記載のものか、またはそれらの組み合わせであり、
前記α7β1インテグリン調節因子は、被験体におけるα7β1インテグリンの発現または活性を、治療前のα7β1インテグリンの発現または活性と比較して増加させることにより、被験体において筋の再生、修復、または維持を促進する、方法。 - 前記α7β1インテグリン調節因子は、被験体が筋損傷または疾患を発症する前に投与される、請求項24に記載の方法。
- 前記方法は、被験体における筋肉維持を促進する方法である、請求項24に記載の方法。
- 前記α7β1インテグリン調節因子は、被験体が運動する前に投与される、請求項26に記載の方法。
- 前記α7β1インテグリン調節因子は、筋疾患または損傷に罹患するリスクのある被験体に投与される、請求項26に記載の方法。
- 筋の再生、修復、または維持を促進する必要のある被験体を選択することをさらに含む、請求項24に記載の方法。
- 前記筋の再生、修復、または維持を促進する必要のある被験体を選択することは、前記α7β1インテグリン調節因子の有効量を被験体に投与する前に、筋再生障害を特徴とする症状のある被験体を診断することを含む、請求項29に記載の方法。
- 前記筋の再生、修復、または維持を促進する必要のある被験体を選択することは、前記α7β1インテグリン調節因子の有効量を被験体に投与する前に、α7β1インテグリンの成分生成障害を特徴とする症状のある被験体を診断することを含む、請求項29に記載の方法。
- 前記α7β1インテグリン調節因子は付加的な治療剤とともに投与される、請求項24に記載の方法。
- 前記付加的な治療剤は、コスタメリックタンパク質、成長因子、サテライト細胞、幹細胞、ミオサイト、または付加的なα7β1インテグリン調節因子である、請求項32に記載の方法。
- 前記付加的なα7β1インテグリン調節因子は、ラミニン−111、ラミニン−111フラグメント、バルプロ酸、またはバルプロ酸アナログである、請求項33に記載の方法。
- 被験体における筋傷害または損傷を予見的に防止または抑制する方法であって、
請求項1〜15のいずれか一項に記載のα7β1インテグリン調節因子またはそれらの組み合わせの有効量を投与することを含み、
前記α7β1インテグリン調節因子により、α7β1インテグリンの発現または活性を、治療前のα7β1インテグリンの発現または活性と比較して増加させることにより、被験体における筋傷害または損傷を予見的に防止または抑制する、方法。 - 前記被験体は筋傷害または損傷を発症するリスクがある、請求項35に記載の方法。
- 前記α7β1インテグリン調節因子は付加的な治療剤とともに投与される、請求項35に記載の方法。
- 前記付加的な治療剤は、コスタメリックタンパク質、成長因子、サテライト細胞、幹細胞、ミオサイト、または付加的なα7β1インテグリン調節因子である、請求項36に記載の方法。
- 前記付加的なα7β1インテグリン調節因子は、ラミニン−111、ラミニン−111フラグメント、バルプロ酸、またはバルプロ酸アナログである、請求項37に記載の方法。
- α7β1インテグリンの発現を促進する方法であって、
細胞をα7β1インテグリン調節因子の有効量と接触させることを含み、
前記α7β1インテグリン調節因子は請求項1〜15のいずれか一項に記載のものか、またはそれらの組み合わせであり、治療後の細胞におけるα7β1インテグリンの発現を未治療の細胞におけるα7β1インテグリンの発現と比較して増加させることにより、α7β1インテグリンの発現を促進する、方法。 - 前記細胞は筋細胞である、請求項30に記載の方法。
- 前記筋細胞は哺乳動物に存在し、前記細胞を薬剤に接触させることは、当該薬剤を当該哺乳動物に投与することを含む、請求項41に記載の方法。
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---|---|---|---|---|
JP2018076267A (ja) * | 2016-11-11 | 2018-05-17 | 花王株式会社 | PPARα活性化剤 |
JP2022506687A (ja) * | 2018-11-06 | 2022-01-17 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
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Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3708564A1 (en) | 2005-12-28 | 2020-09-16 | Vertex Pharmaceuticals Incorporated | A solid form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
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WO2023215367A1 (en) * | 2022-05-04 | 2023-11-09 | Cytokinetics, Inc. | Bicyclic piperazinones and therapeutic uses thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005194198A (ja) * | 2003-12-26 | 2005-07-21 | Takeda Chem Ind Ltd | チエノピリジン化合物 |
WO2007075911A2 (en) * | 2005-12-22 | 2007-07-05 | Yale University | Inhibition of glycogen synthase kinase and methods of treating autoimmune or immune inflammatory disease |
WO2008021210A2 (en) * | 2006-08-11 | 2008-02-21 | Combinatorx, Incorporated | Methods and compositions for the treatment of neurodegenerative disorders |
JP2011500576A (ja) * | 2007-10-09 | 2011-01-06 | ボード オブ リージェンツ オブ ザ ネバダ システム オブ ハイアー エデュケーション オン ビハーフ オブ ザ ユニバーシティ オブ ネバダ リーノー | ラミニン、派生物、及びそれらを含む組成物並びにそれらの治療用途方法 |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991011462A2 (en) | 1990-01-30 | 1991-08-08 | La Jolla Cancer Research Foundation | Merosin, nucleic acids encoding, fragments and uses thereof |
US6283761B1 (en) | 1992-09-08 | 2001-09-04 | Raymond Anthony Joao | Apparatus and method for processing and/or for providing healthcare information and/or healthcare-related information |
US5962427A (en) | 1994-02-18 | 1999-10-05 | The Regent Of The University Of Michigan | In vivo gene transfer methods for wound healing |
DE69738331T2 (de) | 1996-10-08 | 2008-10-16 | University Of Washington, Seattle | Therapeutische anwendungen von laminin und von proteinfragmenten die von laminin abgeleitet sind |
US6933280B2 (en) | 1996-10-08 | 2005-08-23 | Gerardo Castillo | Peptides for the treatment of Alzheimer's disease and other beta-amyloid protein fibrillogenesis disorders |
US6682911B1 (en) | 1997-10-10 | 2004-01-27 | The General Hospital Corporation | Laminins and uses thereof |
US6294356B1 (en) | 1998-01-16 | 2001-09-25 | Northwestern University | Methods and materials for making and using laminin-5 |
US6693169B1 (en) | 1998-10-13 | 2004-02-17 | The General Hospital Corporation | Laminin 5, 13 and 14 and uses thereof |
WO2000055181A1 (en) | 1999-03-15 | 2000-09-21 | The General Hospital Corporation | Methods of modulating cell attachment and migration |
EP1177291A2 (en) | 1999-04-30 | 2002-02-06 | Biostratum, Inc. | Laminin 8 and methods for its use |
AU4496800A (en) | 1999-04-30 | 2000-11-17 | University Of Medicine And Dentistry Of New Jersey | Laminin 2 and methods for its use |
US6703363B1 (en) | 1999-04-30 | 2004-03-09 | Biostratum, Inc. | Recombinant laminin 5 |
WO2002066989A2 (en) | 2001-02-20 | 2002-08-29 | The Board Of Trustees Of The University Of Illinois | Diagnostics, assay methods and amelioration of muscular dystrophy symptoms |
US20050069985A1 (en) | 2001-02-20 | 2005-03-31 | The Board Of Trustees Of The University Of Illinois | Assay methods and amelioration of muscular dystrophy symptoms |
CN1652786A (zh) | 2002-03-13 | 2005-08-10 | 麦克公司 | 作为雄激素受体调节剂的氟代4-氮杂甾体衍生物 |
EP1497410A4 (en) | 2002-04-01 | 2005-05-25 | Peter K Law | CELL TRANSPLANTATION FOR CARDIAC REGENERATION |
US7078379B2 (en) | 2002-06-03 | 2006-07-18 | Santhera Pharmaceuticals (Schweiz) Gmbh | Treatment of congenital muscular dystrophies |
US20060223888A1 (en) | 2002-12-16 | 2006-10-05 | Abbott Frank S | Valproic acid analogues and pharmaceutical composition thereof |
WO2004076631A2 (en) | 2003-02-21 | 2004-09-10 | The Uab Research Foundation | Biologically active native biomatrix composition |
US20050058687A1 (en) | 2003-09-12 | 2005-03-17 | Becton, Dickinson And Company | Covalently attached collagen VI for cell attachment and proliferation |
AU2005233437A1 (en) | 2004-04-12 | 2005-10-27 | Sankyo Company, Limited | Thienopyridine derivatives |
US7749754B2 (en) | 2004-06-09 | 2010-07-06 | The Board Of Trustees Of The Leland Stanford Junior University | Isolation and characterization of muscle regenerating cells |
JP2008501356A (ja) | 2004-06-09 | 2008-01-24 | ザ・ユニバーシティ・コート・オブ・ザ・ユニバーシティ・オブ・エディンバラ | 神経幹細胞 |
US7531355B2 (en) | 2005-07-29 | 2009-05-12 | The Regents Of The University Of California | Methods and compositions for smooth muscle reconstruction |
WO2010080581A2 (en) | 2008-12-19 | 2010-07-15 | The Board Of Regents Of The Nevada System Of Higher Education, On Behalf Of The University Of Nevada, Reno | Valproic acid, derivatives, analogues, and compositions including same and methods for their therapeutic use |
US20110224128A1 (en) | 2009-04-13 | 2011-09-15 | Anne Whalen | Methods and compositions for treatment of muscular dystrophy |
WO2012174126A1 (en) | 2011-06-13 | 2012-12-20 | Universyty Of Medicine And Dentistry Of New Jesey | METHOD OF INHIBITING NONSENSE-MEDIATED mRNA DECAY |
US9782417B2 (en) | 2011-06-16 | 2017-10-10 | Presidents And Fellows Of Harvard College | Methods of increasing satellite cell proliferation with kinase inhibitors |
US9248185B2 (en) | 2011-06-16 | 2016-02-02 | President And Fellows Of Harvard College | Methods of increasing satellite cell proliferation |
EP2825637A4 (en) | 2012-03-14 | 2015-12-23 | Childrens Medical Center | IMAGING-BASED IMAGING HIGH-PERFORMANCE CHEMICAL SCREENING FOR FISH-ZEBRA BLASTOMER CELL CULTURE |
US10398749B2 (en) * | 2012-09-10 | 2019-09-03 | Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno | Methods of treating muscular dystrophy |
US9566310B2 (en) * | 2012-09-10 | 2017-02-14 | Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno | Methods of treating muscular dystrophy |
US9707210B2 (en) * | 2013-03-15 | 2017-07-18 | Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno | Methods of treating muscular dystrophy |
-
2013
- 2013-03-15 US US13/842,781 patent/US9566310B2/en active Active
- 2013-09-10 PL PL13835809T patent/PL2892525T3/pl unknown
- 2013-09-10 EP EP18173735.4A patent/EP3406246A3/en not_active Withdrawn
- 2013-09-10 JP JP2015531326A patent/JP2015527409A/ja active Pending
- 2013-09-10 EP EP13835809.8A patent/EP2892525B1/en not_active Not-in-force
- 2013-09-10 DK DK13835809.8T patent/DK2892525T3/en active
- 2013-09-10 ES ES13835809T patent/ES2688023T3/es active Active
- 2013-09-10 US US14/426,928 patent/US10028992B2/en active Active
- 2013-09-10 CA CA2919516A patent/CA2919516C/en active Active
- 2013-09-10 WO PCT/US2013/059074 patent/WO2014040077A1/en active Application Filing
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- 2016-12-16 US US15/382,448 patent/US10272069B2/en active Active
-
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- 2018-05-14 US US15/979,325 patent/US10398680B2/en active Active
- 2018-08-02 JP JP2018145548A patent/JP2018197252A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005194198A (ja) * | 2003-12-26 | 2005-07-21 | Takeda Chem Ind Ltd | チエノピリジン化合物 |
WO2007075911A2 (en) * | 2005-12-22 | 2007-07-05 | Yale University | Inhibition of glycogen synthase kinase and methods of treating autoimmune or immune inflammatory disease |
WO2008021210A2 (en) * | 2006-08-11 | 2008-02-21 | Combinatorx, Incorporated | Methods and compositions for the treatment of neurodegenerative disorders |
JP2011500576A (ja) * | 2007-10-09 | 2011-01-06 | ボード オブ リージェンツ オブ ザ ネバダ システム オブ ハイアー エデュケーション オン ビハーフ オブ ザ ユニバーシティ オブ ネバダ リーノー | ラミニン、派生物、及びそれらを含む組成物並びにそれらの治療用途方法 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018076267A (ja) * | 2016-11-11 | 2018-05-17 | 花王株式会社 | PPARα活性化剤 |
JP2022506687A (ja) * | 2018-11-06 | 2022-01-17 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
JP2022506685A (ja) * | 2018-11-06 | 2022-01-17 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
JP7162132B2 (ja) | 2018-11-06 | 2022-10-27 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
JP7170133B2 (ja) | 2018-11-06 | 2022-11-11 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
JP7357135B2 (ja) | 2018-11-06 | 2023-10-05 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
JP7429750B2 (ja) | 2018-11-06 | 2024-02-08 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
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US20170224657A1 (en) | 2017-08-10 |
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CA2919516C (en) | 2021-07-27 |
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CA2919516A1 (en) | 2014-03-13 |
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WO2014040077A1 (en) | 2014-03-13 |
US20150290276A1 (en) | 2015-10-15 |
US9566310B2 (en) | 2017-02-14 |
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EP2892525B1 (en) | 2018-06-13 |
US10272069B2 (en) | 2019-04-30 |
EP3406246A3 (en) | 2019-03-27 |
JP2018197252A (ja) | 2018-12-13 |
EP2892525A1 (en) | 2015-07-15 |
EP2892525A4 (en) | 2016-08-03 |
PL2892525T3 (pl) | 2018-11-30 |
US20180263959A1 (en) | 2018-09-20 |
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