JP2016522817A - アポリポタンパク質(a)発現を調節するための組成物および方法 - Google Patents
アポリポタンパク質(a)発現を調節するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、配列表とともに電子形式で出願されている。この配列表は、2014年5月1日に作成された432KbのサイズのBIOL0250WOSEQ_ST25.txtという名前のファイルとして提供される。この配列表の電子形式の情報は、参照によりその全体が本明細書に組み込まれる。
Aは、アンチセンスオリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Cは、共役リンカーであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
同一の環上、独立して、各環のR3とR4の各対について、R3が、Hおよび−OCH2CH2OCH3から選択され、R4が、Hであるか、またはR3およびR4が一緒になって橋を形成するかのいずれかであり、そこで、R3が、−O−であり、R4が、−CH2−、−CH(CH3)−、または−CH2CH2−であり、結果として生じる橋が、−O−CH2−、−O−CH(CH3)−、および−O−CH2CH2−から選択されるように、R3およびR4が直接連結され、
R5が、Hおよび−CH3から選択され、
Zが、S−およびO−から選択される。
本開示は、以下の非限定的な番号付けされた実施形態を提供する。
A.定義
本明細書で使用されるとき、「ヌクレオシド」とは、核酸塩基部分および糖部分を含む化合物を意味する。ヌクレオシドには、天然に存在するヌクレオシド(DNAおよびRNAに見られるもの)ならびに修飾ヌクレオシドが含まれるが、これらに限定されない。ヌクレオシドは、ホスフェート部分に連結され得る。
RaおよびRdは各々、独立して、O、S、CH2、NH、またはNJ1であり、J1は、C1〜C6アルキルまたは置換C1〜C6アルキルであり、
Rbは、OまたはSであり、
Rcは、OH、SH、C1〜C6アルキル、置換C1〜C6アルキル、C1〜C6アルコキシ、置換C1〜C6アルコキシ、アミノ、または置換アミノであり、
J1は、Rbが、OまたはSである。
非ヌクレオシド間リン結合基は、ヌクレオシドをヌクレオシド以外の基に結合させる。
非ヌクレオシド間リン結合基は、2個の基を結合するが、これらはいずれもヌクレオシドではない。
本明細書で使用されるとき、「切断可能な結合」とは、分割され得る任意の化学結合を意味する。ある特定の実施形態において、切断可能な結合は、アミド、ポリアミド、エステル、エーテル、ホスホジエステルの一方もしくは両方のエステル、リン酸エステル、カルバメート、ジスルフィド、またはペプチドの中から選択される。
ある特定の実施形態
同一の環上、独立して、各環のR3とR4の各対について、R3が、Hおよび−OCH2CH2OCH3から選択され、R4が、Hであるか、またはR3およびR4が一緒になって橋を形成するかのいずれかであり、そこで、R3が、−O−であり、R4が、−CH2−、−CH(CH3)−、または−CH2CH2−であり、結果として生じる橋が、−O−CH2−、−O−CH(CH3)−、および−O−CH2CH2−から選択されるように、R3およびR4が直接連結され、
R5が、Hおよび−CH3から選択され、
Zが、S−およびO−から選択される。
Z1は、C(=O)O−R2であり、
Z2は、H、C1〜C6アルキル、または置換C1〜C6アルキであり、
R2は、H、C1〜C6アルキルまたは置換C1〜C6アルキであり、
各m1は、独立して、0〜20であり、少なくとも1つのm1は、各テザーに対して0を超える。
各m1は、独立して、0〜20であり、少なくとも1つのm1は、各テザーに対して0を超える。
Aは、修飾オリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Cは、共役リンカーであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、修飾オリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Cは、共役リンカーであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
各nは、独立して、0または1であり、
qは、1〜5の整数である。
ある特定の実施形態において、化合物は、以下の式によって表される構造を有し、
Aは、修飾オリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Cは、共役リンカーであり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、修飾オリゴヌクレオチドであり、
Cは、共役リンカーであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、修飾オリゴヌクレオチドであり、
Cは、共役リンカーであり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、修飾オリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、修飾オリゴヌクレオチドであり、
Bは、切断可能な部分であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、修飾オリゴヌクレオチドであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Z1は、C(=O)O−R2であり、
Z2は、H、C1〜C6アルキル、または置換C1〜C6アルキであり、
R2は、H、C1〜C6アルキルまたは置換C1〜C6アルキであり、
各m1は、独立して、0〜20であり、少なくとも1つのm1は、各テザーに対して0を超える。
各pは、1〜約6である。
Q13は、HまたはO(CH2)2−OCH3であり、
Aは、修飾オリゴヌクレオチドであり、
Bxは、複素環式塩基部分である。
Q13は、HまたはO(CH2)2−OCH3であり、
Aは、修飾オリゴヌクレオチドであり、
Bxは、複素環式塩基部分である。
Q13は、HまたはO(CH2)2−OCH3であり、
Aは、修飾オリゴヌクレオチドであり、
Zは、Hまたは結合固体支持体であり、
Bxは、複素環式塩基部分である。
Q13は、HまたはO(CH2)2−OCH3であり、
Aは、修飾オリゴヌクレオチドであり、
Zは、Hまたは結合固体支持体であり、
Bxは、複素環式塩基部分である。
B.ある特定の化合物
a.ある特定のアンチセンスオリゴヌクレオチド
i.ある特定の化学的特徴
1.ある特定の糖部分
式中、
xは、0、1、または2であり、
nは、1、2、3、または4であり、
各RaおよびRbは、独立して、H、保護基、ヒドロキシル、C1〜C12アルキル、置換C1〜C12アルキル、C2〜C12アルケニル、置換C2〜C12アルケニル、C2〜C12アルキニル、置換C2〜C12アルキニル、C5〜C20アリール、置換C5〜C20アリール、複素環式ラジカル、置換複素環式ラジカル、ヘテロアリール、置換ヘテロアリール、C5〜C7脂環式ラジカル、置換C5〜C7脂環式ラジカル、ハロゲン、OJ1、NJ1J2、SJ1、N3、COOJ1、アシル(C(=O)−H)、置換アシル、CN、スルホニル(S(=O)2−J1)、またはスルホキシル(S(=O)−J1)であり、
各J1およびJ2は、独立して、H、C1〜C12アルキル、置換C1〜C12アルキル、C2〜C12アルケニル、置換C2〜C12アルケニル、C2〜C12アルキニル、置換C2〜C12アルキニル、C5〜C20アリール、置換C5〜C20アリール、アシル(C(=O)−H)、置換アシル、複素環式ラジカル、置換複素環式ラジカル、C1〜C12アミノアルキル、置換C1〜C12アミノアルキル、または保護基である。
Bxは、核酸塩基部分であり、
T3およびT4は各々、独立して、テトラヒドロピランヌクレオシド類似体をアンチセンス化合物に結合させるヌクレオシド間結合基であるか、またはT3およびT4のうちの一方は、テトラヒドロピランヌクレオシド類似体をアンチセンス化合物に結合させるヌクレオシド間結合基であり、T3およびT4のうちの他方は、H、ヒドロキシル保護基、結合共役基、または5’もしくは3’−末端基であり、
q1、q2、q3、q4、q5、q6、およびq7は各々、独立して、H、C1〜C6アルキル、置換C1〜C6アルキル、C2〜C6アルケニル、置換C2〜C6アルケニル、C2〜C6アルキニル、または置換C2〜C6アルキニルであり、
R1およびR2の各々は、水素、ハロゲン、置換または非置換アルコキシ、NJ1J2、SJ1、N3、OC(=X)J1、OC(=X)NJ1J2、NJ3C(=X)NJ1J2、およびCNの中から独立して選択され、式中、Xは、O、S、またはNJ1であり、各J1、J2、およびJ3は、独立して、HまたはC1〜C6アルキルである。
2.ある特定の核酸塩基修飾
3.ある特定のヌクレオシド間結合
4.ある特定のモチーフ
a.ある特定の糖モチーフ
i.ある特定の5’−ウィング
ii.ある特定の3’−ウィング
iii.ある特定の中央領域(ギャップ)
b.ある特定のヌクレオシド間結合モチーフ
c.ある特定の核酸塩基修飾モチーフ
d.ある特定の全長
5.ある特定のアンチセンスオリゴヌクレオチドの化学的モチーフ
i.ある特定の配列および標的
ii.ある特定の切断可能な部分
iii.ある特定のリンカー
1.ある特定の分岐基
Z1は、C(=O)O−R2であり、
Z2は、H、C1〜C6アルキル、または置換C1〜C6アルキであり、
R2は、H、C1〜C6アルキル、または置換C1〜C6アルキであり、
各m1は、独立して、0〜20であり、少なくとも1つのm1は、各テザーに対して0を超える。
各m1は、独立して、0〜20であり、少なくとも1つのm1は、各テザーに対して0を超える。
3.ある特定のリガンド
Zは、Hまたは結合固体支持体であり、
Qは、アンチセンス化合物であり、
Xは、OまたはSであり、
Bxは、複素環式塩基部分である。
Aは、アンチセンスオリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Cは、共役リンカーであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、アンチセンスオリゴヌクレオチドであり、
Cは、共役リンカーであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
ある特定のそのような実施形態において、共役リンカーは、少なくとも1個の切断可能な結合を含む。
ある特定のそのような実施形態において、分岐基は、少なくとも1個の切断可能な結合を含む。
ある特定の実施形態において、各テザーは、少なくとも1個の切断可能な結合を含む。
Aは、アンチセンスオリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Cは、共役リンカーであり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、アンチセンスオリゴヌクレオチドであり、
Cは、共役リンカーであり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、アンチセンスオリゴヌクレオチドであり、
Bは、切断可能な部分であり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
Aは、アンチセンスオリゴヌクレオチドであり、
Dは、分岐基であり、
各Eは、テザーであり、
各Fは、リガンドであり、
qは、1〜5の整数である。
C.ある特定の用途および特徴
D.アンチセンス
C.アポリポタンパク質(a)(apo(a))
Apo(a)核酸を標的にするある特定の共役アンチセンス化合物
Apo(a)治療指標
Apo(a)治療集団
D.ある特定の医薬組成物
参照による非限定的な開示および組み込み
実施例1:ホスホラミダイト(化合物1、1a、および2)の調製のための一般的方法
実施例2:化合物7の調製
実施例3:化合物11の調製
実施例5:化合物23の調製
実施例10:5’末端にGalNAc3−1を含む共役ASO(化合物34)の一般的調製
実施例11:化合物39の調製
実施例12:化合物40の調製
実施例19:固相技法による3’位にGalNAc3−1を含む共役ASOの調製のための一般的方法(ISIS 647535、647536、および651900の調製)
実施例20:huApoC IIIトランスジェニックマウスにおけるヒトApoC IIIの用量依存的アンチセンス阻害
処理
ApoC III mRNA分析
ApoC IIIタンパク質分析(比濁アッセイ)
薬物動態分析(PK)
処理
実施例22:生体内におけるSRB−1を標的とするGalNAc3−1共役修飾ASOの影響
処理
実施例23:ヒト末梢血単核細胞(hPBMC)アッセイプロトコル
実施例24:hPBMCアッセイにおけるGalNAc3−1共役ASOの炎症誘発作用の評価
実施例26:ApoC III ASO活性へのPO/PS結合の影響
実施例28:化合物60の調製
実施例29:化合物63の調製
実施例30:化合物63bの調製
実施例31:化合物63dの調製
実施例32:化合物67の調製
実施例33:化合物70の調製
実施例34:化合物75aの調製
実施例36:化合物79aの調製
実施例37:固体支持体による5’末端にホスホジエステル結合GalNAc3−2共役体を含む共役オリゴマー化合物82の調製のための一般的方法(方法I)
実施例38:5’末端にホスホジエステル結合GalNAc3−2共役体を含むオリゴマー化合物82の調製のための代替方法(方法II)
実施例39:固体支持体による5’末端にGalNAc3−3共役体(5’末端結合のためにGalNAc3−1修飾されたもの)を含むオリゴマー化合物83hの調製のための一般的方法
実施例40:固体支持体による3’末端にホスホジエステル結合GalNAc3−4共役体を含むオリゴマー化合物89の調製のための一般的方法
実施例41:固相技法による5’位にホスホジエステル結合GalNAc3−2(Bxがアデニンである実施例37を参照のこと)共役体を含むASOの調製のための一般的方法(ISIS 661134の調製)
その後、非結合ASOを濾過し、アンモニアを沸去した。残渣を強力なアニオン交換カラム上での高圧液体クロマトグラフィーによって精製した(GE Healthcare Bioscience、Source 30Q、30μm、2.54×8cm、A=30%CH3CN水溶液中100mM酢酸アンモニウム、B=A中1.5M NaBr、60分後0〜40%のB、流量14mL/分−1、λ=260nm)。残渣を逆相カラム上でのHPLCにより脱塩して、固体支持体への初期充填に基づいて15〜30%の単離収率で所望のASOを得た。ASOを、Agilent 1100 MSDシステムを用いたイオン対HPLCカップリングMS分析によって特徴付けた。
実施例42:固相技法による5’位にGalNAc3−3共役体を含むASOの調製のための一般的方法(ISIS 661166の調製)
実施例43:生体内におけるSRB−1を標的とする5’末端でのホスホジエステル結合GalNAc3−2の用量依存的試験(Bxがアデニンである実施例37および41を参照のこと)
処理
薬物動態分析(PK)
実施例44:SRB−1を標的とする3’末端にGalNAc3−1共役体(実施例9を参照のこと)を含むASOのアンチセンス阻害へのPO/PS結合の影響
処理
実施例46:PFPエステル(オリゴヌクレオチド111)との共役のための一般的手順;ISIS 666881(GalNAc3−10)の調製
実施例47:GalNAc3−8を含むオリゴヌクレオチド102の調製
実施例54:化合物18(GalNAc3−1aおよびGalNAc3−3a)の調製のための代替手順
実施例55:生体内におけるSRB−1を標的とする3’−共役基または5’−共役基のいずれかを含むオリゴヌクレオチドの用量依存的試験(GalNAc3−1、3、8、および9の比較)
処理
処理
実施例58:生体内におけるSRB−1を標的とする3’−共役基を含むオリゴヌクレオチドの用量依存的試験(GalNAc3−1およびGalNAc4−11の比較)
処理
処理
処理
処理
処理
処理
実施例76:GalNAc3−23を含むオリゴマー化合物230の調製
処理
処理
処理
処理
処理
実施例83:GalNAc3クラスターを含む第XI因子を標的とするオリゴヌクレオチドによる生体内におけるアンチセンス阻害
処理
処理
処理
処理
処理
処理
実施例88:GalNAc3共役体を含むSMNを標的とするオリゴヌクレオチドによる生体内におけるスプライシング調節
処理
処理
処理
処理
実施例93:混合ウィングおよび5’−GalNAc3共役体を含むSRB−1を標的とするオリゴヌクレオチドによる生体内におけるアンチセンス阻害
処理
処理
処理
実施例98:hPMBCアッセイにおけるGalNAc共役体を含むオリゴヌクレオチドの炎症誘発作用の評価
処理
実施例102:GalNAc共役体を含むアンチセンスオリゴヌクレオチドの肝臓における分布
処理
処理
処理
実施例114:トランスジェニックマウス初代肝細胞におけるヒトapo(a)のアンチセンス阻害
実施例116:トランスジェニックマウス初代肝細胞におけるapo(a)の時間依存的アンチセンス阻害
実施例119:ヒトapo(a)トランスジェニックマウスにおけるヒトapo(a)の生体内におけるアンチセンス阻害の影響
研究1
ヒトapo(a)mRNAの阻害
ヒトapo(a)タンパク質の阻害
研究2
処理
ヒトapo(a)mRNAの阻害
研究3
処理
ヒトapo(a)mRNAの阻害
ヒトapo(a)タンパク質レベルの低下
研究4
処理
ヒトapo(a)mRNAの阻害
処理
ヒトapo(a)mRNAの阻害
CD1マウスにおける耐容性:研究1
処理
血漿化学マーカー
処理
血漿化学マーカー
実施例121:CD1マウスにおけるアンチセンスオリゴヌクレオチドの薬物動態
処理
オリゴヌクレオチド濃度の測定
処理
オリゴヌクレオチド濃度の測定
標的減少
RNA分析
処理
RNA分析
Claims (193)
- 修飾オリゴヌクレオチドおよび共役基を含む化合物であって、前記修飾オリゴヌクレオチドが、12〜30個の連結したヌクレオシドからなり、かつ配列番号1の核酸塩基3901〜3920の等長部分に相補的な少なくとも8個の連続した核酸塩基の一部を含む核酸塩基配列を含み、前記修飾オリゴヌクレオチドの前記核酸塩基配列が、配列番号1に少なくとも80%相補的である、化合物。
- 前記修飾オリゴヌクレオチドが、配列番号1の等長部分に相補的な少なくとも10、少なくとも12、少なくとも14、少なくとも16、少なくとも18、少なくとも19、または少なくとも20個の連続した核酸塩基の一部を含む核酸塩基配列を含む、請求項1に記載の化合物。
- 修飾オリゴヌクレオチドおよび共役基を含む化合物であって、前記修飾オリゴヌクレオチドが、12〜30個の連結したヌクレオシドからなり、かつ配列番号1の核酸塩基3900〜3923の等長部分に相補的な少なくとも8、少なくとも10、少なくとも12、少なくとも14、少なくとも15、または少なくとも16個の連続した核酸塩基の一部を含む核酸塩基配列を含み、前記修飾オリゴヌクレオチドの前記核酸塩基配列が、配列番号1に少なくとも80%相補的である、化合物。
- 前記修飾オリゴヌクレオチドの前記核酸塩基配列が、配列番号1に少なくとも85%、少なくとも90%、少なくとも95%、または100%相補的である、請求項1〜3のいずれかに記載の化合物。
- 修飾オリゴヌクレオチドおよび共役基を含む化合物であって、前記修飾オリゴヌクレオチドが、12〜30個の連結したヌクレオシドからなり、かつ配列番号58の核酸塩基配列の少なくとも8、最小9、最小10、最小11、少なくとも12、最小13、少なくとも14、少なくとも15、少なくとも16、最小17、最小18、最小19、または20個の連続した核酸塩基を含む核酸塩基配列を有する、化合物。
- 修飾オリゴヌクレオチドおよび共役基を含む化合物であって、前記修飾オリゴヌクレオチドが、12〜30個の連結したヌクレオシドからなり、かつ配列番号12〜130、133、134の核酸塩基配列のうちのいずれかの少なくとも8、最小9、最小10、最小11、少なくとも12、最小13、少なくとも14、少なくとも15、少なくとも16、最小17、最小18、最小19、または20個の連続した核酸塩基を含む核酸塩基配列を有する、化合物。
- 前記修飾オリゴヌクレオチドが一本鎖である、請求項1〜6のいずれかに記載の化合物。
- 前記修飾オリゴヌクレオチドが二本鎖である、請求項1〜6のいずれかに記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも1個の修飾ヌクレオシド間結合を含む、請求項1〜のいずれかに記載の化合物。
- 前記修飾ヌクレオシド間結合がホスホロチオエートヌクレオシド間結合である、請求項9に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも1個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも2個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも3個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも4個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも5個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも6個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドが少なくとも7個のホスホジエステルヌクレオシド間結合を含む、請求項10に記載の化合物。
- 前記修飾オリゴヌクレオチドの各ヌクレオシド間結合が、ホスホジエステルヌクレオシド間結合およびホスホロチオエートヌクレオシド間結合から選択される、請求項11〜17のいずれかに記載の化合物。
- 前記修飾オリゴヌクレオチドの各ヌクレオシド間結合が、ホスホロチオエートヌクレオシド間結合を含み、ホスホロチオエートヌクレオシド間結合である、請求項1〜8のいずれかに記載の化合物。
- ISIS 494372および共役基からなる化合物。
- 前記修飾オリゴヌクレオチドが少なくとも1個の修飾糖を含む、請求項1〜20のいずれかに記載の化合物。
- 少なくとも1個の修飾糖が二環糖である、請求項21に記載の化合物。
- 少なくとも1個の修飾糖が、2’−O−メトキシエチル、拘束エチル、3’−フルオロ−HNA、または4’−(CH2)n−O−2’橋を含み、式中、nが、1または2である、請求項21に記載の化合物。
- 少なくとも1個のヌクレオシドが、修飾核酸塩基を含む、請求項1〜23のいずれかに記載の化合物。
- 前記修飾核酸塩基が5−メチルシトシンである、請求項24に記載の化合物。
- 前記修飾オリゴヌクレオチドが、12〜30個の連結したヌクレオシドからなり、かつ
連結したデオキシヌクレオシドからなるギャップセグメントと、
連結したヌクレオシドからなる5’ウィングセグメントと、
連結したヌクレオシドからなる3’ウィングセグメントと、を含み、
前記ギャップセグメントが、前記5’ウィングセグメントと前記3’ウィングセグメントとの間に位置付けられ、各ウィングセグメントの各ヌクレオシドが、修飾糖を含む、請求項1〜25のいずれかに記載の化合物。 - 前記修飾オリゴヌクレオチドが、15〜30、18〜24、19〜22、13〜25、14〜25、15〜25、16、または20個の連結したヌクレオシドからなる、請求項1〜26のいずれかに記載の化合物。
- 修飾オリゴヌクレオチドおよび共役基を含む化合物であって、前記修飾オリゴヌクレオチドが、20個の連結したヌクレオシドからなり、かつ配列番号58のうちのいずれかの等長部分に相補的なa少なくとも8個の連続した核酸塩基を含む核酸塩基配列を有し、前記修飾オリゴヌクレオチドが、
10個の連結したデオキシヌクレオシドからなるギャップセグメントと、
5個の連結したヌクレオシドからなる5’ウィングセグメントと、
5個の連結したヌクレオシドからなる3’ウィングセグメントと、を含み、
前記ギャップセグメントが、前記5’ウィングセグメントと前記3’ウィングセグメントとの間に位置付けられ、各ウィングセグメントの各ヌクレオシドが、2’−O−メトキシエチル糖を含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシン残基が、5−メチルシトシンである、化合物。 - 前記共役基が、前記修飾オリゴヌクレオチドの5’末端で前記修飾オリゴヌクレオチドに連結される、請求項1〜28のいずれかに記載の化合物。
- 前記共役基が、前記修飾オリゴヌクレオチドの3’末端で前記修飾オリゴヌクレオチドに連結される、請求項1〜28のいずれかに記載の化合物。
- 前記共役基が、正確に1個のリガンドを含む、請求項1〜30のいずれかに記載の化合物。
- 前記共役基が、正確に2個のリガンドを含む、請求項1〜30のいずれかに記載の化合物。
- 前記共役基が、3個以上のリガンドを含む、請求項1〜30のいずれかに記載の化合物。
- 前記共役基が、正確に3個のリガンドを含む、請求項1〜30のいずれかに記載の化合物。
- 各リガンドが、多糖、修飾多糖、糖、修飾多糖、マンノース、ガラクトース、マンノース誘導体、ガラクトース誘導体、D−マンノピラノース、L−マンノピラノース、D−アラビノース、L−ガラクトース、D−キシロフラノース、L−キシロフラノース、D−グルコース、L−グルコース、D−ガラクトース、L−ガラクトース、α−D−マンノフラノース、β−D−マンノフラノース、α−D−マンノピラノース、β−D−マンノピラノース、α−D−グルコピラノース、β−D−グルコピラノース、α−D−グルコフラノース、β−D−グルコフラノース、α−D−フルクトフラノース、α−D−フルクトピラノース、α−D−ガラクトピラノース、β−D−ガラクトピラノース、α−D−ガラクトフラノース、β−D−ガラクトフラノース、グルコサミン、シアル酸、α−D−ガラクトサミン、N−アセチルガラクトサミン、2−アミノ−3−O−[(R)−1−カルボキシエチル]−2−デオキシ−β−D−グルコピラノース、2−デオキシ−2−メチルアミノ−L−グルコピラノース、4,6−ジデオキシ−4−ホルムアミド−2,3−ジ−O−メチル−D−マンノピラノース、2−デオキシ−2−スルホアミノ−D−グルコピラノース、N−グリコロイル−α−ノイラミン酸、5−チオ−β−D−グルコピラノース、メチル2,3,4−トリ−O−アセチル−1−チオ−6−O−トリチル−α−D−グルコピラノシド、4−チオ−β−D−ガラクトピラノース、エチル3,4,6,7−テトラ−O−アセチル−2−デオキシ−1,5−ジチオ−α−D−グルコ−ヘプトピラノシド、2,5−アンヒドロ−D−アロノニトリル、リボース、D−リボース、D−4−チオリボース、L−リボース、L−4−チオリボースの中から選択される、請求項31〜34のいずれかに記載の化合物。
- 各リガンドがN−アセチルガラクトサミンである、請求項35に記載の化合物。
- 前記共役基が、少なくとも1個のリン結合基または中性結合基を含む、請求項30〜36のいずれかに記載の化合物。
- 前記共役基が、前記修飾オリゴヌクレオチドに共有結合される、請求項1〜46のいずれかに記載の化合物。
- 前記共役リンカーがピロリジンを含む、請求項48〜61のいずれかに記載の化合物。
- 前記共役リンカーがピロリジンを含まない、請求項48〜61のいずれかに記載の化合物。
- 前記共役リンカーがPEGを含む、請求項48〜63のいずれかに記載の化合物。
- 前記共役リンカーがアミドを含む、請求項48〜64のいずれかに記載の化合物。
- 前記共役リンカーが少なくとも2個のアミドを含む、請求項48〜64のいずれかに記載の化合物。
- 前記共役リンカーがアミドを含まない、請求項48〜64のいずれかに記載の化合物。
- 前記共役リンカーがポリアミドを含む、請求項48〜67のいずれかに記載の化合物。
- 前記共役リンカーがアミンを含む、請求項48〜68のいずれかに記載の化合物。
- 前記共役リンカーが1個以上のジスルフィド結合を含む、請求項48〜69のいずれかに記載の化合物。
- 前記共役リンカーがタンパク質結合部分を含む、請求項48〜70のいずれかに記載の化合物。
- 前記タンパク質結合部分が脂質を含む、請求項71に記載の化合物。
- 前記タンパク質結合部分が、コレステロール、コール酸、アダマンタン酢酸、1−ピレン酪酸、ジヒドロテストステロン、1,3−ビス−O(ヘキサデシル)グリセロール、ゲラニルオキシヘキシル基、ヘキサデシルグリセロール、ボルネオール、メントール、1,3−プロパンジオール、ヘプタデシル基、パルミチン酸、ミリスチン酸、O3−(オレオイル)リトコール酸、O3−(オレオイル)コレン酸、ジメトキシトリチル、またはフェノキサジン)、ビタミン(例えば、葉酸塩、ビタミンA、ビタミンE、ビオチン、ピリドキサール)、ペプチド、炭水化物(例えば、単糖、二糖、三糖、四糖、オリゴ糖、多糖)、エンドソーム溶解成分、ステロイド(例えば、ウバオール、ヘシゲニン、ジオスゲニン)、テルペン(例えば、トリテルペン、例えば、サルササポゲニン、フリーデリン、エピフリーデラノール誘導体化リトコール酸)、またはカチオン性脂質の中から選択される、請求項71に記載の化合物。
- 前記タンパク質結合部分が、C16〜C22長鎖飽和もしくは不飽和脂肪酸、コレステロール、コール酸、ビタミンE、アダマンタン、または1−ペンタフルオロプロピルの中から選択される、請求項71に記載の化合物。
- 前記分岐基がエーテルを含む、請求項48〜81のいずれかに記載の化合物。
- 少なくとも1個のテザーがエチレングリコールを含む、請求項48〜93のいずれかに記載の化合物。
- 少なくとも1個のテザーがアミドを含む、請求項48〜93または95のいずれかに記載の化合物。
- 少なくとも1個のテザーがポリアミドを含む、請求項48〜93または95のいずれかに記載の化合物。
- 少なくとも1個のテザーがアミンを含む、請求項48〜93または95のいずれかに記載の化合物。
- 少なくとも2個のテザーが互いに異なる、請求項48〜93または95のいずれかに記載の化合物。
- 前記テザーのすべてが互いに同一である、請求項48〜93または95のいずれかに記載の化合物。
- 前記リガンドがガラクトースである、請求項47〜108のいずれかに記載の化合物。
- 前記リガンドがマンノース−6−ホスフェートである、請求項47〜108のいずれかに記載の化合物。
- 前記共役基が細胞標的部分を含む、請求項1〜30または56〜81のいずれかに記載の化合物。
- 前記共役基が、ホスホジエステル、アミド、またはエステルの中から選択される切断可能な部分を含む、請求項1〜147のいずれかに記載の化合物。
- 前記共役基が、ホスホジエステル切断可能な部分を含む、請求項1〜147のいずれかに記載の化合物。
- 前記共役基が、切断可能な部分を含まず、前記共役基が、前記共役基と前記オリゴヌクレオチドとの間にホスホロチオエート結合を含む、請求項1〜147のいずれかに記載の化合物。
- 前記共役基が、アミド切断可能な部分を含む、請求項1〜150のいずれかに記載の化合物。
- 前記共役基が、エステル切断可能な部分を含む、請求項1〜150のいずれかに記載の化合物。
- Bxが、アデニン、グアニン、チミン、ウラシル、またはシトシン、もしくは5−メチルシトシンの中から選択される、請求項153〜170のいずれかに記載の化合物。
- Bxがアデニンである、請求項153〜170のいずれかに記載の化合物。
- Bxがチミンである、請求項153〜170のいずれかに記載の化合物。
- Q13がO(CH2)2−OCH3である、請求項153〜170のいずれかに記載の化合物。
- Q13がHである、請求項153〜170のいずれかに記載の化合物。
- 以下の式
式中、R1が、−OCH2CH2OCH3(MOE)であり、R2が、Hであるか、またはR1およびR2が一緒になって橋を形成するかのいずれかであり、そこで、R1が、−O−であり、R2が、−CH2−、−CH(CH3)−、または−CH2CH2−であり、結果として生じる橋が、−O−CH2−、−O−CH(CH3)−、および−O−CH2CH2−から選択されるように、R1およびR2が直接連結され、
同一の環上、独立して、各環のR3とR4の各対について、R3が、Hおよび−OCH2CH2OCH3から選択され、R4が、Hであるか、またはR3およびR4が一緒になって橋を形成するかのいずれかであり、そこで、R3が、−O−であり、R4が、−CH2−、−CH(CH3)−、または−CH2CH2−であり、結果として生じる橋が、−O−CH2−、−O−CH(CH3)−、および−O−CH2CH2−から選択されるように、R3およびR4が直接連結され、
R5が、Hおよび−CH3から選択され、
Zが、S−およびO−から選択される、化合物。 - 請求項1〜179のいずれかに記載の前記化合物またはその塩と、薬剤的に許容される担体または希釈剤のうちの少なくとも1つと、を含む、組成物。
- 請求項1〜180のいずれかに記載の前記化合物を含むプロドラッグ。
- 動物に請求項1〜181のいずれかに記載の前記化合物または組成物を投与することを含む、方法。
- 前記動物がヒトである、請求項181に記載の方法。
- 前記化合物の投与が、心臓血管、代謝性、および/もしくは炎症性疾患行を予防するか、治療するか、改善するか、またはその進行を遅らせる、請求項181に記載の方法。
- 前記化合物または組成物と第2の薬剤を共投与することを含む、請求項182に記載の方法。
- 前記化合物または組成物と前記第2の薬剤が同時に投与される、請求項185に記載の方法。
- 前記投与が非経口投与である、請求項176に記載の方法。
- 前記投与が皮下投与である、請求項176に記載の方法。
- 動物におけるapo(a)mRNAまたはタンパク質発現を減少させる方法であって、前記動物に請求項1〜181のいずれかに記載の前記化合物または組成物を投与して、前記動物におけるapo(a)mRNAまたはタンパク質発現を減少させることを含む、方法。
- 動物におけるLp(a)レベルを減少させる方法であって、前記動物に請求項1〜181のいずれかに記載の前記化合物または組成物を投与して、前記動物におけるapo(a)mRNAまたはタンパク質発現を減少させることを含む、方法。
- 治療に用いるための請求項1〜190のいずれかに記載の前記化合物を含む組成物。
- apo(a)の上昇および/またはLp(a)の上昇に関連した疾患を治療するか、予防するか、またはその進行を遅らせる際に用いられる、請求項191に記載の化合物。
- 前記疾患が、炎症性、心臓血管、もしくは代謝性疾患、障害、または状態である、請求項191に記載の化合物。
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