JP6072058B2 - 顆粒球コロニー刺激因子受容体と結合する方法および組成物 - Google Patents
顆粒球コロニー刺激因子受容体と結合する方法および組成物 Download PDFInfo
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Description
本願は、その内容がそのまま本願明細書に組み込まれる、発明の名称が、各々、「顆粒球コロニー刺激因子受容体と結合する方法および組成物」である、2011年11月18日出願の米国仮特許出願第61/561510号および2011年11月14日出願の米国仮特許出願第61/559660号の利益を主張する。
本願は電子フォーマットで配列表を添付して出願されている。配列表は、2012年10月29日に作成された、ファイル名「LIGAND200WO.TXT」で提供され、その大きさは約3Kbである。配列表の電子フォーマットの情報はそのまま本明細書の中に組み込まれる。
化学および医学の分野における組成物および方法が開示される。開示されている実施態様のいくつかは顆粒球コロニー刺激因子受容体(GCFR)の活性を制御する組成物である。開示されている実施態様のいくつかは顆粒球コロニー刺激因子受容体(GCFR)の活性を制御する化合物の使用または確認方法である。開示されている実施態様のいくつかは、顆粒球コロニー刺激因子受容体(GCFR)と関連付けられる造血障害または神経障害などの特定の障害を治療するための化合物の使用を包含する。
R1は、水素、OR6、NO2、CN、NR6R7、CO2R6、C(=O)NR6R7、SO3R6、SO2NR6R8、所望により置換されてもよいC1−C6アルキル、所望により置換されてもよいC2−C6アルケニル、所望により置換されてもよいC2−C6アルキニル、所望により置換されてもよいC1−C6ヘテロアルキル、所望により置換されてもよいC3−C6シクロアルキル、所望により置換されてもよいC3−C6シクロアルケニル、所望により置換されてもよいC2−C6ヘテロシクリル、所望により置換されてもよいアリールアルキル、所望により置換されてもよいアリール、および所望により置換されてもよいヘテロアリールより選択され;
R10は、所望により置換されてもよいC1−C12アルキル、所望により置換されてもよいC1−C12ヘテロアルキル、所望により置換されてもよいC2−C12ヘテロアルケニル、所望により置換されてもよいC2−C12ヘテロアルキニル、所望により置換されてもよいC1−C12シクロアルキル、所望により置換されてもよいC1−C6ヘテロシクロアルキル、所望により置換されてもよいヘテロアリールアルキル、所望により置換されてもよいアリールヘテロアルキル、所望により置換されてもよいヘテロアリールヘテロアルキル、OR14、SR14、およびNR8R14より選択され;
R1は、水素、OR6、NO2、CN、NR6R7、CO2R6、C(=O)NR6R7、SO3R6、SO2NR6R8、所望により置換されてもよいC1−C6アルキル、所望により置換されてもよいC2−C6アルケニル、所望により置換されてもよいC2−C6アルキニル、所望により置換されてもよいC1−C6ヘテロアルキル、所望により置換されてもよいC3−C6シクロアルキル、所望により置換されてもよいC3−C6シクロアルケニル、所望により置換されてもよいC2−C6ヘテロシクリル、所望により置換されてもよいアリールアルキル、所望により置換されてもよいアリール、および所望により置換されてもよいヘテロアリールより選択され;
R10は、所望により置換されてもよいC1−C12アルキル、所望により置換されてもよいC1−C12ヘテロアルキル、所望により置換されてもよいC2−C12ヘテロアルケニル、所望により置換されてもよいC2−C12ヘテロアルキニル、所望により置換されてもよいC1−C12シクロアルキル、所望により置換されてもよいC1−C6ヘテロシクロアルキル、所望により置換されてもよいヘテロアリールアルキル、所望により置換されてもよいアリールヘテロアルキル、所望により置換されてもよいヘテロアリールヘテロアルキル、OR14、SR14、およびNR8R14より選択され;
特に定義されない限り、本明細書に記載の、実験操作、ならびに分析化学、合成有機化学、および医学および製薬化学の技術と関連して使用される命名法は、当該分野にて公知の方法である。標準的な化学記号はかかる記号で表される正式な名称と互換的に使用される。かくして、例えば、「水素」と「H」なる語は同じ意味を有すると理解される。標準的な方法が、化学合成、化学分析、製剤調製、処方、送達および患者の治療に使用されてもよい。標準的な方法が組換えDNA、オリゴヌクレオチド合成および組織培養および形質転換(例えば、エレクトロポレーション、リポフェクション)に使用されてもよい。反応および精製方法は、例えば、製造業者の仕様説明書に従ってキットを用いて、あるいは当該分野にて一般に成し遂げられるように、または本明細書に記載されるように実施されてもよい。上記した技法および操作は、一般に、当該分野にて周知の慣用的方法、および本願明細書を通して引用かつ検討されている種々の一般的でより具体的な文献に記載される方法に従って実施されてもよい。例えば、その内容がそのまま本願明細書に組み込まれる、Sambrookら、Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989))を参照のこと。
を包含するが、これらに限定されない。
R1は、水素、OR6、NO2、CN、NR6R7、CO2R6、C(=O)NR6R7、SO3R6、SO2NR6R8、所望により置換されてもよいC1−C6アルキル、所望により置換されてもよいC2−C6アルケニル、所望により置換されてもよいC2−C6アルキニル、所望により置換されてもよいC1−C6ヘテロアルキル、所望により置換されてもよいC3−C6シクロアルキル、所望により置換されてもよいC3−C6シクロアルケニル、所望により置換されてもよいC2−C6ヘテロシクリル、所望により置換されてもよいアリールアルキル、所望により置換されてもよいアリール、および所望により置換されてもよいヘテロアリールより選択され;
R1は、水素、所望により置換されてもよいC1−C6アルキル、所望により置換されてもよいC3−C6シクロアルキル、所望により置換されてもよいC3−C6シクロアルケニル、所望により置換されてもよいC2−C6ヘテロシクリル、所望により置換されてもよいアリール、および所望により置換されてもよいヘテロアリールより選択され;
R3は、水素、所望により置換されてもよいC1−C6アルキル、所望により置換されてもよいC3−C8シクロアルキル、所望により置換されてもよいC1−C6ヘテロシクリル、所望により置換されてもよいアリール、および所望により置換されてもよいヘテロアリールより選択され;
R1は、水素、OR6、NR6R7、CO2R6、C(=O)NR6R7、所望により置換されてもよいC2−C6ヘテロシクリル、所望により置換されてもよいアリールアルキル、所望により置換されてもよいアリール、および所望により置換されてもよいヘテロアリールより選択され;
R4は、所望により置換されてもよいC1−C6アルキル、所望により置換されてもよいC3−C8シクロアルキル、所望により置換されてもよいC1−C6ヘテロシクリル、所望により置換されてもよいアリール、所望により置換されてもよいヘテロアリール、所望により置換されてもよいアリールアルキル、および所望により置換されてもよいヘテロアリールアルキルより選択され;
R10は、所望により置換されてもよいC1−C12アルキル、所望により置換されてもよいC1−C12ヘテロアルキル、所望により置換されてもよいC2−C12ヘテロアルケニル、所望により置換されてもよいC2−C12ヘテロアルキニル、所望により置換されてもよいC1−C12シクロアルキル、所望により置換されてもよいC1−C6ヘテロシクロアルキル、所望により置換されてもよいヘテロアリールアルキル、所望により置換されてもよいアリールヘテロアルキル、所望により置換されてもよいヘテロアリールヘテロアルキル、OR14、SR14、およびNR8R14より選択され;
で示される互変異性型またはその医薬上許容される塩で存在しうる。
で示される互変異性型またはその医薬上許容される塩で存在しうる。
ある実施態様において、選択的GCSFRモジュレーターあるいはその医薬上許容される塩、エステル、アミドおよび/またはプロドラッグは、単独で、または1または複数の医薬上許容される担体と組み合わせて、医薬剤を形成する。本発明の実施態様の化合物を処方および投与する技法は、例えば、「Remington's Pharmaceutical Sciences」, Mack Publishing Co., Easton, PA, 第18版, 1990(その内容がそのまま本願明細書に組み込まれる)に見ることができる。
ある実施態様において、本発明の実施態様の1または複数の医薬剤は、1または複数の他の医薬剤と共投与される。ある実施態様において、かかる1または複数の他の医薬剤は本発明の実施態様の1または複数の医薬剤と同じ疾患または症状を治療することを目的とする。ある実施態様において、かかる1または複数の他の医薬剤は本発明の実施態様の1または複数の医薬剤と異なる疾患または症状を治療することを目的とする。ある実施態様において、かかる1または複数の他の医薬剤は本発明の実施態様の1または複数の医薬剤の望ましくない作用を治療することを目的とする。ある実施態様において、本発明の実施態様の1または複数の医薬剤はその他の医薬剤の望ましくない作用を治療するために他の医薬剤と共投与される。ある実施態様において、本発明の実施態様の1または複数の医薬剤、および1または複数の他の医薬剤は同時に投与される。
ある実施態様において、本発明の実施態様の1または複数の医薬剤、および1または複数の他の医薬剤は別々の時に投与される。ある実施態様において、本発明の実施態様の1または複数の医薬剤、および1または複数の他の医薬剤は単一の製剤にて一緒に調製される。ある実施態様において、本発明の実施態様の1または複数の医薬剤、および1または複数の他の医薬剤は別々に調製される。
ある実施態様は、造血障害または神経障害などの障害を治療または改善する方法を包含する。かかる方法は治療または改善が必要な対象に本明細書に記載の有効量の化合物を投与することを包含し得る。本明細書に記載の化合物を用いて治療され得る障害の例として、顆粒球減少症、好中球減少症、筋萎縮性側索硬化症、多発性硬化症、多発性ジストロフィー(multiple dystrophy)、脊髄損傷などの神経系の損傷、および外傷または脳卒中から由来の損傷が挙げられる。ある実施態様において、障害は顆粒球減少症を包含しうる。顆粒球減少症は化学療法、放射線治療、骨髄移植の失敗、および/または再生不良性貧血よりもたらされうる。
本明細書に記載の方法のある実施態様は、治療用化合物を確認することを包含する。かかる治療用化合物は、GCSFRアゴニストなどの、顆粒球形成を刺激する化合物を包含する。かかる実施態様は、GCSFRの活性を選択的にモジュレートする化合物を確認することを包含する。ある実施態様において、治療用化合物は、野生型GCSFRタンパク質と比べて、変異GCSFRタンパク質の存在下で活性の減少した化合物を包含する。かかる実施態様にて、変異GCSFRは、GCSFRタンパク質の膜貫通ドメインにて変異を、あるいはGCSFRタンパク質の膜貫通ドメインの近くに変異を含む。
4−アミノ−4−オキソ酪酸N’−(1−フェニル−1−(1−(3,5−ジメトキシフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)メチル)ヒドラジド(化合物101)
4−アミノ−4−オキソ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)ペンチル)ヒドラジド(化合物102)
4−アミノ−4−オキソ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)ブチル)ヒドラジド(化合物103)
シクロペンタンカルボン酸N’−(1−フェニル−1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)メチル)ヒドラジド(化合物104)
3−アセチルアミノプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物105)
4−アミノ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物106)
(5−アミノ−1−テトラゾール)酢酸N’−(1−フェニル−1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)メチル)ヒドラジド(化合物107)
(1−テトラゾール)酢酸N’−(1−フェニル−1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)メチル)ヒドラジド(化合物108)
(±)−(1−ベンジル−2−オキソ−5−ピロリジン)カルボン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物109)
4−アミノ−4−オキソ酪酸N’−(1−(1−(3−メトキシフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物110)
4−アミノ−4−オキソ酪酸N’−(1−(1−(3,5−ジメトキシフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物111)
4−ジメチルアミノ−4−オキソ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物112)
4−ヒドロキシシクロヘキシル−1−カルボン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物113)
5−ヒドロキシ−5−オキソペンタン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物114)
3−アミノ−3−オキソプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物115)
(±)−(2−オキソ−3−ピペリジン)カルボン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物116)
4−アミノ−4−オキソ酪酸N’−(1−フェニル−1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)メチル)ヒドラジド(化合物117)
3−(1−ピラゾール)プロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物118)
4−ヒドロキシ−4−オキソ酪酸N’−(1−(1−(4−メチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物119)
4−ヒドロキシ酪酸N’−(1−フェニル−1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)メチル)ヒドラジド(化合物123)
シクロプロピルカルボン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)−1−(2−フリル)メチル)ヒドラジド(化合物124)
4−ヒドロキシ酪酸N’−(1−(1−(3−トリフルオロメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物126)
4−アミノ−4−オキソ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物128)
4−フェニルアミノ−4−オキソ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物129)
3−メトキシプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物133)
3−ヒドロキシプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物138)
3−ジメチルアミノプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物145)
(±)−3−ヒドロキシ酪酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物147)
シクロプロピルカルボン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物148)
(±)−2−ヒドロキシプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物151)
3−エトキシ−3−オキソプロピオン酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物153)
2−(4−ヒドロキシフェニル)酢酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)エチル)ヒドラジド(化合物156)
ウレイド酢酸N’−(1−(1−(3,5−ジメチルフェニル)−2−オキソ−6−トリフルオロメチル−1,2−ジヒドロインドール−3(Z)−イリデン)−1−フェニルメチル)ヒドラジド(化合物159)
1−(3−ヒドロキシプロピル)−3−メチル−5−オキソ−4,5−ジヒドロ−4−(2−ヒドロキシ−3−(2−(2,6−ジメチルフェニル)−エチル)フェニルヒドラゾノ)ピラゾ−ル(化合物161)
1−(2−ヒドロキシエチル)−3−メチル−5−オキソ−4,5−ジヒドロ−4−(2−ヒドロキシ−3−(2−(2,5−ジメチルフェニル)−エチル)フェニルヒドラゾノ)ピラゾ−ル(化合物162)
1−(4−ヒドロキシブチル)−3−メチル−5−オキソ−4,5−ジヒドロ−4−(2−ヒドロキシ−3−(2(E)−(2−メチルフェニル)−エテニル)フェニルヒドラゾノ)ピラゾ−ル(化合物163)
1−(3−ヒドロキシプロピル)−3−メチル−5−オキソ−4,5−ジヒドロ−4−(2−ヒドロキシ−3−(2−(2,5−ジメチルフェニル)−エチル)フェニルヒドラゾノ)ピラゾ−ル(化合物164)
1−(4−ヒドロキシブチル)−3−メチル−5−オキソ−4,5−ジヒドロ−4−(2−ヒドロキシ−3−(2−(2,6−ジメチルフェニル)−エチニル)フェニルヒドラゾノ)ピラゾ−ル(化合物165)
ある実施態様において、特定のアッセイを用いて、本実施態様の化合物のGCSFR調整活性のレベルを測定してもよい。ある実施態様において、選択的に変異させたGCSFRを含むアッセイを用いて、該化合物とTMドメインとの相互作用を測定してもよい。ある実施態様において、ヒトとは異なる種(例えば、マウスまたはサル)から由来のGCSFRを含むアッセイを用いて化合物の活性を測定してもよい。
いくつかの実施態様において、内因的に、あるいは安定した、または一時的なトランスフェクションによるかのいずれかで、GCSFRを発現する細胞株であって、その成長についてGCSFに依存してもよい細胞株を用いるインビトロ増殖アッセイにて、化合物を試験する。細胞を計数することにより、あるいは細胞増殖のマーカーとしてのATPの産生を測定するアッセイを用いることにより、該化合物の細胞増殖に対する活性を測定する。
いくつかの実施態様において、内因的に、あるいは安定した、または一時的なトランスフェクションによりGCSFRを発現する細胞株を用いるレポーターアッセイにて、化合物を試験する。これらの細胞は、GCSF応答性レポーター(ルシフェラーゼ等)で安定して、または一時的にトランスフェクトされ、その化合物の活性は細胞中のレポーターの数を測定することにより決定される。
いくつかの実施態様において、化合物を精製されたヒトCD34+骨髄細胞にて試験する。化合物を細胞に添加した後、造血、赤血球生成、顆粒球生成、血小板生成、または骨髄造血のマーカーを発現する細胞の数を、フローサイトメトリーにより、これら経路に関係する遺伝子の発現を解析することにより、あるいはこれらの経路に特異的な細胞(例えば、赤血球または顆粒球)のコロニー形成を測定することによって測定する。ある実施態様において、ヒト以外の他の種(例えば、マウスまたはサル)から由来の骨髄細胞で化合物を試験する。
ヒトGCSF受容体(hGCSFR)アッセイ
ルシフェラーゼレポーターアッセイを用いてhGCSFRを活性化する化合物を確認した。ヒト細胞株(例えば、MCF−7乳癌細胞、HepG2肝癌細胞またはHEK293腎細胞)に、hGCSFRcDNAをCMVプロモーターの下流に含有するhGCSFR発現プラスミドを、およびGCSF応答性因子を最小チミジンキナーゼプロモーターの上流に含有するルシフェラーゼレポータープラスミドを、一時的にトランスフェクトした。ルシフェラーゼレポーターアッセイでは、96ウェルのマイクロタイタープレート中、10%ウシ胎児血清(FBS)含有のイーグル最小必須培地(EMEM)に細胞を入れた。その翌日に、hGCSFR発現プラスミドおよびルシフェラーゼレポータープラスミドを、FuGene6トランスフェクション試薬(Roche、インディアナポリス、インディアナ州)をその仕様説明書に従って用いて細胞に一時的にトランスフェクトした。明くる日に、培地を1%FBSおよび10μM塩化亜鉛を含有する培地と交換した。四日目に、組換えhGCSF(rhGCSF)を(200ng/mlの最大濃度で)または試験化合物を(10μMの最大濃度で)含有する培地を2回重複して該細胞に添加した。6時間後、細胞より該培地を除去し、該細胞を界面活性剤含有の緩衝液に溶解させた。細胞抽出液中のルシフェラーゼ活性を測定し、転写活性化のレベルを決定した。ルシフェリン含有緩衝液を96ウェルプレートの各ウェルに加え、ルミノメータ−を用いてルシフェラーゼ活性を測定した。
ルシフェラーゼレポーターアッセイを用い、化合物の、変異hGCSFR、mGCSFR、または変異mGCSFRを活性化する能力を測定した。ヒト細胞株(例えば、MCF−7乳癌細胞、HepG2肝癌細胞またはHEK293腎細胞)に3種のGCSFR発現プラスミド:1)hGCSFR TMドメインのヒスチジン−627をコードするヌクレオチドが、ヒスチジン−627の同じ位置にマウスGCSFRのアスパラギン−602として存在するアスパラギンをコードするように改変されている、hGCSFR cDNAを含有するhGCSFR発現プラスミド;2)mGCSFR cDNAをCMVプロモーターの下流に含有するmGCSFR発現プラスミド;3)mGCSFR TMドメインのアスパラギン−602をコードするヌクレオチドがヒスチジンをコードするように改変されている、mGCSFR cDNAを含有するmGCSFR発現プラスミド、の一つを一時的にトランスフェクトした。ルシフェラーゼレポーターアッセイでは、96ウェルのマイクロタイタープレート中、10%ウシ胎児血清(FBS)含有のイーグル最小必須培地(EMEM)に細胞を入れた。その翌日に、3種のGCSFR発現プラスミドの一つおよびルシフェラーゼレポータープラスミドを、FuGene6トランスフェクション試薬(Roche、インディアナポリス、インディアナ州)をその仕様説明書に従って用いて細胞に一時的にトランスフェクトした。明くる日に、培地を1%FBSおよび10μM塩化亜鉛を含有する培地と交換した。四日目に、rhGCSFを(200ng/mlの最大濃度で)または試験化合物を(10μMの最大濃度で)含有する培地を2回重複して該細胞に添加した。6時間後、細胞より該培地を除去し、該細胞を界面活性剤含有の緩衝液に溶解させた。細胞抽出液中のルシフェラーゼ活性を測定し、転写活性化のレベルを決定した。ルシフェリン含有緩衝液を96ウェルプレートの各ウェルに加え、ルミノメータ−を用いてルシフェラーゼ活性を測定した。
ViaLight(登録商標)Plusキット(Cambrex)またはATPliteキット(Roche)を用いる増殖アッセイを用い、化合物の、細胞の成長に対する活性を確立した。UT−7ヒト白血病細胞株(Komatsu N, Nakauchi H, Miwa A, Ishihara T, Eguchi M, Moroi M, Okada M, Sato Y, Wada H, Yawata Y, Suda T, Miura Y: Establishment and characterization of a human leukemic cell line with megakaryocytic features: Dependency on granulocyte-macrophage colony-stimulating factor, Interleukin 3, or erythropoietin for growth and survival. Cancer Res 51: 341, 1991)は、hGCSFR発現プラスミドで安定的にトランスフェクトされた。hGCSFRを発現する安定したクローン(UT7−hPG細胞)を同定し、10%FBS、rhGM−CSFおよびG418を含有する培地中で成長かつ維持させた。該アッセイでは、UT7−hPG細胞はrhGM−CSFが一夜不足しており、96ウェルプレートで、10%FBSおよび10μM亜鉛を含有する培地に置いた。rhGCSFを(200ng/mlの最大濃度で)または試験化合物を(10μMの最大濃度で)含有する培地を2回重複して該細胞に添加した。48時間後、細胞の増殖をViaLight(登録商標)Plusキットを製造業者プロトコルに従って用いて測定した。細胞を10分間にわたって界面活性剤含有緩衝液に溶解させ、次にATPモニター試薬を添加して発光シグナルを発生させた。該シグナルを細胞抽出液中の相対的な光単位として測定し、細胞の増殖のレベルを決定した。
競合結合アッセイを用いて、組換えヒトGCSF(rhGCSF)のhGCSFRへの結合に対する化合物の活性を測定した。該アッセイでは、UT7−hPG細胞は、2%FBS含有の培地にてrhGM−CSFが4時間不足しており、96ウェルのv型底プレートで、2%FBS、10μM亜鉛および0.1%アジ化ナトリウムを含有する培地に置いた。rhGCSFを(200ng/mlの最大濃度で)または試験化合物を(10μMの最大濃度で)含有する培地を2回重複して該細胞に添加した。室温で1時間経過した後、0.05nMの最終濃度までの[125I]標識のrhGCSF(NEX−426、Perkin Elmer)を含有する培地を該細胞に加え、該細胞をロッキングプラットフォーム上室温で2時間インキュベートした。該細胞を冷リン酸緩衝セイラインで2回洗浄し、細胞をトリトンX−100含有の緩衝液で溶解させた。その溶解物をシンチレーションバイアルに移し、シンチレーション液を加え、バイアル中の放射線量(カウント毎分)をシンチレーションカウンターで測定した。
ヒト骨髄顆粒球分化アッセイを用い、ヒト骨髄CD34+細胞のCD15陽性(CD15+)顆粒球への分化を誘発するrhGCSFまたは試験化合物の能力を測定した。キャンブレックスからの精製された正常なヒト骨髄CD34+細胞をこのアッセイで用いた。該細胞を、0.1ng/mlのrhGCSFと共に、または無しで、3日間、10%ウシ胎児血清(FBS)、0.5ng/mLの幹細胞因子(SCF)を含有する培地で培養した。細胞を洗浄し、12ウェルプレート中、10%FBSおよび0.5ng/mlのSCFを含有する培地に入れた。rhGCSFを(100ng/mlの最大濃度で)または試験化合物を(1μMの最大濃度で)2回重複して添加し、細胞をさらに7日間培養した。該細胞を抗CD15抗体またはアイソタイプ対照で染色し、フローサイトメトリーで解析した。活性をCD15+細胞%として決定し、最大rhGCSF応答のパーセンテージで表す。EC50を化合物の用量応答曲線より決定し、効能を100ng/mlのrhGCSFと比較することで計算した。加えて、rhGCSFまたは試験化合物のCD34+細胞に対する効果を、rhGCSFまたは化合物で7日間インキュベートした後、ATPlite(登録商標)キットを用いて測定した。
GCSFは好中性顆粒球を制御するサイトカインである。GCSFはホモ二量体受容体(GCSFR)に対して作用し、顆粒球前駆細胞の増殖を刺激し、その生存および好中球への分化を誘発する。組換えヒトGCSF(rhGCSF)をうまく用い、重度の慢性好中球減少症ならびに化学療法により誘発されるか、または造血幹細胞移植に付随する好中球減少症を緩和する。小分子の経口用GCSFアゴニストは、現在の注射可能なrhGCSF療法と比べてより安全で、より都合のよい代替法を提供する。リード化合物X等の、ヒトGCSFR(hGCSFR)機能を選択的に活性化し、好中球減少症の治療にて有意なイノベーションを提供し得る、一連の新規な非ペプチジル小分子が見つかった。
ルシフェラーゼレポーターアッセイ:
HepG2またはHEK293細胞を、hGCSFR、hTPOR、hEPOR、マウスGCSFRまたは変異受容体についての発現ベクターで、およびSTAT3応答性またはSTAT5応答性ルシフェラーゼレポーターのいずれかで一時的にトランスフェクトした。細胞を、溶解およびルシフェラーゼ測定に付す前の6時間、ビヒクル、rhGCSF(Neupogen(登録商標))、rhTPO(R&D system)、rhEPO(Epogen(登録商標))または化合物Xで処理した。
UT7親細胞をネオマイシン耐性遺伝子を含有するhGCSFR発現ベクターでトランスフェクトし、クローンをG418に対する耐性により確認した。hGCSFに対して反応するサブクローン(UTP−hGCSFR)が確認された。
UT7−TPO、UT7−EPOまたはUTP−hGCSFR細胞をビヒクル、rhGCSF、rhTPO、rhEPOまたは化合物Xで48時間処理した。生存をATPlight(登録商標)(PerkinElmer)でアッセイした。
CD34陽性ヒト骨髄細胞を、ヒト幹細胞因子(hSCF、R&D Systems)を補足した培地中、ビヒクル、rhGCSFまたは化合物Xと共に7日間培養した。細胞を抗CD15(BD Biosciences)で染色し、FACSで解析した。
細胞をビヒクル、rhGCSFまたは化合物Xと共に種々の時間培養し、AlphaScreen(登録商標)SureFire(登録商標)アッセイキット(PerkinElmer)を用いてホスホ−STAT3およびホスホ−STAT5を測定した。
UTP−hGCSFR細胞を、[125I]rhGCSF(PerkinELmer)を共にrhGCSFまたは化合物Xの存在下または不在下、室温で2時間インキュベートした。細胞を2回洗浄し、放射線量をシンチレーションカウンターで測定した。
化合物Xは、hGCSFR発現ベクターで共トランスフェクトされた細胞中、STAT3およびSTAT5陽性ルシフェラーゼレポーターを活性化した(図1Aおよび図1B)。化合物XはトランスフェクトされたhGCSFRの不在下ではいずれのレポーターも活性化しなかった(図示せず)。化合物Xは、hTPORまたはhEPOR発現ベクターでトランスフェクトされたHEK293細胞中、STAT5陽性ルシフェラーゼレポーターを活性化しなかった(図2Aおよび図2B)。
考察
Claims (8)
- 式(III):
R1は、水素、OR6、NO2、CN、NR6R7、CO2R6、C(=O)NR6R7、SO3R6、SO2NR6R8、置換されてもよいC1−C6アルキル、置換されてもよいC2−C6アルケニル、置換されてもよいC2−C6アルキニル、置換されてもよいC1−C6ヘテロアルキル、置換されてもよいC3−C6シクロアルキル、置換されてもよいC3−C6シクロアルケニル、置換されてもよいC2−C6ヘテロシクリル、置換されてもよいアリールアルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R 2 は、独立して、水素、置換されてもよいC1−C6アルキル、置換されてもよいC2−C6アルケニル、置換されてもよいC2−C6アルキニル、置換されてもよいC1−C6ヘテロアルキル、置換されてもよいC3−C8シクロアルキル、置換されてもよいC3−C8シクロアルケニル、置換されてもよいC1−C6ヘテロシクリル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R4は、水素、置換されてもよいC1−C6アルキル、置換されてもよいC2−C6アルケニル、置換されてもよいC2−C6アルキニル、置換されてもよいC1−C6ヘテロアルキル、置換されてもよいC3−C8シクロアルキル、置換されてもよいC3−C8シクロアルケニル、置換されてもよいC1−C6ヘテロシクリル、置換されてもよいアリール、置換されてもよいヘテロアリール、置換されてもよいアリールアルキル、置換されてもよいアリールアルケニル、置換されてもよいアリールアルキニル、および置換されてもよいヘテロアリールアルキルより選択され;
R5は、NO2、CN、CF3、OR6、CO2R6、C(=O)NR6R7、SO3R6、SO2NR6R8、置換されてもよいアリール、置換されてもよいC1−C6アルキル、および置換されてもよいC1−C6ヘテロアルキルより選択され;
R6は、水素、置換されてもよいC1−C6アルキル、C1−C6ヘテロアルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R7は、水素、C(=O)R8、C(=O)NHR8、置換されてもよいC1−C6アルキル、および置換されてもよいC1−C6ヘテロアルキルより選択されるか;または−NR6R7は環窒素を介して結合した置換されてもよい非芳香族ヘテロシクリルであり;
R8は、水素、置換されてもよいC1−C6アルキル、および置換されてもよいC1−C6ヘテロアルキルより選択され;
Qは、NR6、置換されてもよいC1−C6アルキル、置換されてもよいC3−C8シクロアルキル、置換されてもよいC1−C6ヘテロアルキル、および置換されてもよい非芳香族ヘテロシクリルからなる群より選択され;
L1はNHおよびCHR2より選択され;
ZはO(酸素)であり;
nは1、2または3である;
ただし、式(III)において、R2がメチル、R4がフェニル、L1がNHであって、QがN−Ph−R1である場合、式(III)のR1はハロゲン、アルキル、置換アルキル、カルボン酸およびカルボン酸エステルからなる群より選択されない]
で示される化合物、その互変異性体、またはその医薬上許容される塩。 - 式(IIIa):
R1は、水素、OR6、NR6R7、CO2R6、C(=O)NR6R7、置換されてもよいC2−C6ヘテロシクリル、置換されてもよいアリールアルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R2は、水素、置換されてもよいC1−C6アルキル、置換されてもよいC3−C8シクロアルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R4は、水素、置換されてもよいC1−C6アルキル、置換されてもよいアリール、置換されてもよいヘテロアリール、置換されてもよいアリールアルキル、および置換されてもよいヘテロアリールアルキルより選択され;
R5は、CN、CF3、OR6、置換されてもよいアリール、および置換されてもよいC1−C6アルキルより選択され;
R6は、水素、置換されてもよいC1−C6アルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R7は、水素、C(=O)R8、C(=O)NHR8、および置換されてもよいC1−C6アルキルより選択されるか;または−NR6R7は環窒素を介して結合した置換されてもよい非芳香族ヘテロシクリルであり;
R8は、水素、および置換されてもよいC1−C6アルキルより選択され;
Qは、NR6、置換されてもよいC1−C6アルキル、置換されてもよいC3−C8シクロアルキル、および置換されてもよい非芳香族ヘテロシクリルより選択され;
ZはO(酸素)であり;および
nは1または2である]
で示される構造を有する、請求項1記載の化合物、その互変異性体、またはその医薬上許容される塩。 - R1が、水素、OR6、NR6R7、CO2R6、C(=O)NR6R7、置換されてもよいC2−C6ヘテロシクリル、置換されてもよいアリールアルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R2が、水素、置換されてもよいC1−C6アルキル、置換されてもよいC3−C8シクロアルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R4が、水素、置換されてもよいC1−C6アルキル、置換されてもよいアリール、置換されてもよいヘテロアリール、置換されてもよいアリールアルキル、および置換されてもよいヘテロアリールアルキルより選択され;
R5が、CN、CF3、OR6、置換されてもよいアリール、および置換されてもよいC1−C6アルキルより選択され;
R6が、水素、および置換されてもよいC1−C6アルキルより選択され;
R7が、水素、C(=O)R8、C(=O)NHR8、および置換されてもよいC1−C6アルキルより選択され;
R8が、水素、および置換されてもよいC1−C6アルキルより選択され;
Qが、NR6、置換されてもよいC1−C4アルキル、置換されてもよいC3−C6シクロアルキル、および置換されてもよい非芳香族ヘテロシクリルより選択され;
ZがO(酸素)であり;および
nが1である、
請求項2記載の化合物。 - R1が、水素、OR6、NR6R7、C(=O)NR6R7、置換されてもよいアリールアルキル、および置換されてもよいヘテロアリールより選択され;
R2が、水素、置換されてもよいC1−C6アルキル、置換されてもよいアリール、および置換されてもよいヘテロアリールより選択され;
R4が置換されてもよいアリールであり;
R5が、CN、CF3、OR6、置換されてもよいアリール、および置換されてもよいC1−C6アルキルより選択され;
R6が、水素、および置換されてもよいC1−C3アルキルより選択され;
R7が、水素、C(=O)R8、C(=O)NHR8、および置換されてもよいC1−C3アルキルより選択され;
R8が、水素、および置換されてもよいC1−C3アルキルより選択され;および
Qが、置換されてもよいC1−C3アルキル、置換されてもよいC3−C6シクロアルキル、および置換されてもよい非芳香族ヘテロシクリルより選択される、
請求項3記載の化合物。 - 請求項1〜4のいずれか一項に記載の化合物および医薬上許容される賦形剤を含む、医薬組成物。
- 請求項1〜4のいずれか一項に記載の化合物を含む、造血障害または神経障害を治療するための医薬組成物であって、該障害が、顆粒球減少症、好中球減少症、筋萎縮性側索硬化症、多発性硬化症、多発性ジストロフィー(multiple dystrophy)、および脊髄損傷からなる群より選択される、医薬組成物。
- 該化合物が化学療法、骨髄移植および放射線療法からなる群より選択されるさらなる治療方法と組み合わせて投与される、請求項6記載の化合物。
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