JP2021501754A - インテグリンリガンドおよびその使用 - Google Patents
インテグリンリガンドおよびその使用 Download PDFInfo
- Publication number
- JP2021501754A JP2021501754A JP2020524155A JP2020524155A JP2021501754A JP 2021501754 A JP2021501754 A JP 2021501754A JP 2020524155 A JP2020524155 A JP 2020524155A JP 2020524155 A JP2020524155 A JP 2020524155A JP 2021501754 A JP2021501754 A JP 2021501754A
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- αvβ6 integrin
- integrin ligand
- optionally substituted
- room temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003446 ligand Substances 0.000 title claims abstract description 396
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- 108010044426 integrins Proteins 0.000 title claims abstract description 378
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- 125000000547 substituted alkyl group Chemical group 0.000 claims description 35
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- 108090000623 proteins and genes Proteins 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000004429 atom Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
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- 125000003118 aryl group Chemical group 0.000 claims description 20
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
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- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
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- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 2
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- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
本出願は、2017年11月1日に出願された米国特許仮出願第62/580,398号、2018年3月22日に出願された米国特許仮出願第62/646,739号、および2018年6月1日に出願された米国特許仮出願第62/679,549号(各々の内容全体が、本明細書中で参考として援用される)の優先権を主張する。
上皮細胞が含まれる種々の細胞型で発現されるインテグリンアルファ−vベータ−6(αvβ6)は、TGF−βの潜在関連ペプチド(LAP)ならびに細胞外基質(ECM)タンパク質であるフィブロネクチン、ビトロネクチン、およびテネイシンの受容体である。αvβ6インテグリンは、健常成人の上皮で辛うじて検出可能であるが、創傷治癒中および様々な癌(例えば、結腸癌、卵巣癌、子宮内膜癌、および胃癌癌)で上方制御され、しばしば、癌の予後不良に関連する。αvβ6インテグリンは、転移における細胞浸潤および細胞遊走を促進し、アポトーシスを阻害することができることが示されている。αvβ6インテグリンはまた、マトリックスメタロプロテアーゼ(MMP)の発現を制御し、TGF−β1を活性化することができる。αvβ6インテグリンが癌腫の進行を促進する可能性があることを示唆する、主にin vitro研究に由来する証拠が増加しつつある。したがって、インテグリンαvβ6は、とりわけ、マトリックスメタロプロテアーゼ(MMP)の発現およびTGF−β1の活性化におけるその役割の観点から、腫瘍バイオマーカーおよび潜在的な治療標的として魅力的である。
新規の合成αvβ6インテグリンリガンド(本明細書中でαvβ6リガンドとも呼ばれる)を本明細書中に記載する。本明細書中に開示のαvβ6インテグリンリガンドは、血清中で安定であり、αvβ6インテグリンに親和性を有し、かつ特異的に結合することができる。αvβ6インテグリンリガンドをカーゴ分子に結合して、αvβ6インテグリンを発現する所望の細胞または組織(上皮細胞など)へのカーゴ分子の送達を容易にすることができる。
nは0〜7の整数であり;
JはC−HまたはNであり;
Zは、OR13、N(R13)2、またはSR13であり;
R1は、H、必要に応じて置換されたC1〜C6アルキル、OH、COOH、CON(R5)2、OR6であるか、R1は、カーゴ分子を含み、ここで、各R5は、独立して、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2、RP1、およびRP2は、各々独立して、H、ハロ、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、または必要に応じて置換されたヘテロアリーレンであるか、R2、RP1、およびRP2は、カーゴ分子を含んでよく;
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
各R13は、独立して、H、必要に応じて置換されたアルキルであるか、R13は、カーゴ分子を含み;
R14は必要に応じて置換されたアルキルであり;
ここで、R1、R2、R13、RP1、およびRP2のうちの少なくとも1つは、カーゴ分子を含む)の構造物またはその薬学的に許容され得る塩を含む。
αvβ6インテグリンリガンド。
血清安定性およびインテグリンαvβ6に対する親和性を有する合成αvβ6インテグリンリガンドを本明細書中に記載する。αvβ6インテグリンリガンドを使用して、in vitro、in situ、ex vivo、および/またはin vivoでインテグリンαvβ6を発現する細胞を標的にすることができる。いくつかの実施形態では、本明細書中に開示のαvβ6インテグリンリガンドは、1またはそれを超えるカーゴ分子に結合され、in vitro、in situ、ex vivo、および/またはin vivoでインテグリンαvβ6を発現する細胞にカーゴ分子を優先的に指向して標的にすることができる。いくつかの実施形態では、カーゴ分子は、薬学的に活性な化合物を含むかそれからなる。いくつかの実施形態では、カーゴ分子は、RNAi剤などのオリゴヌクレオチド系化合物を含むか、それからなる。いくつかの実施形態では、本明細書中に開示のαvβ6インテグリンリガンドは、in vivoでカーゴ分子を上皮細胞に指向させるためにカーゴ分子に結合される。
nは0〜7の整数であり;
JはC−HまたはNであり;
Zは、OR13、N(R13)2、またはSR13であり;
R1は、H、必要に応じて置換されたC1〜C6アルキル、OH、COOH、CON(R5)2、OR6であるか、R1は、カーゴ分子を含み、ここで、各R5は、独立して、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2、RP1、およびRP2は、各々独立して、H、ハロ、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、または必要に応じて置換されたヘテロアリーレンであるか、R2、RP1、およびRP2は、カーゴ分子を含んでよく;
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
各R13は、独立して、H、必要に応じて置換されたアルキルであるか、R13は、カーゴ分子を含み;
R14は必要に応じて置換されたアルキルであり;
ここで、R1、R2、R13、RP1、およびRP2のうちの少なくとも1つは、カーゴ分子を含む)の構造物またはその薬学的に許容され得る塩を含む。
nは、0〜7の整数であり(すなわち、nは、0、1、2、3、4、5、6、または7である);
JはC−HまたはNであり;
R1は、H、C1〜C6アルキル、CH(R3)(R4)、OH、COOH、CH2CH2CH2NH2、CONHR5、OR6であり、ここで、R3は、HまたはC1〜C6アルキルであり、R4は、H、C1〜C6アルキルであり、R5は、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2は、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、または必要に応じて置換されたヘテロアリーレンであり、
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
R13は、Hまたは必要に応じて置換されたアルキルであり;
R14は必要に応じて置換されたアルキルであり;
ここで、R1またはR2のうちの少なくとも1つはカーゴ分子を含む)の構造物またはその薬学的に許容され得る塩を含む。
nは、1〜7の整数であり(すなわち、nは、1、2、3、4、5、6、または7である);
R7は、1またはそれを超えるカーゴ分子を含み;
R8は、2、3、4、5、6、7、8、9、または10個の炭素原子を有する1またはそれを超える必要に応じて置換された2価の環状部分(シクロアルキル(例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、またはシクロヘプチル)、シクロアルケニル(例えば、シクロペンテニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、またはシクロヘプテニル)、アリール(例えば、フェニル)、ヘテロアリール(例えば、ピリジル、ピリミジニル、ピリダジニル、ピロール、ピラゾール、イミダゾール、チオフェン、ベンゾチオフェン、チアゾール、ベンゾチアゾール、フラン、オキサゾール、イソキサゾール、ベンゾフラン、インドール、インダゾール、ベンズイミダゾール、オキサジアゾール、1,2,3−トリアゾール、1,2,4−トリアゾール、テトラゾール、キノリニル、イソキノリニル、またはキノキサリニル)、またはヘテロシクリル(例えば、テトラヒドロフラン、テトラヒドロピラン、ピペリジン、ピロリジン、ジオキサン、またはジオキソラン)など)である)の構造物またはその薬学的に許容され得る塩を含む。
nは、1〜7の整数であり(すなわち、nは、1、2、3、4、5、6、または7である);
R9は、1またはそれを超えるカーゴ分子を含む)の構造物またはその薬学的に許容され得る塩を含む。
nは0〜7の整数であり;
JはC−HまたはNであり;
Zは、OR13、N(R13)2、またはSR13であり;
R1は、H、必要に応じて置換されたC1〜C6アルキル、OH、COOH、CON(R5)2、OR6であるか、R1は、反応基に結合した連結基を含み、ここで、各R5は、独立して、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2、RP1、およびRP2は、各々独立して、H、ハロ、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、または必要に応じて置換されたヘテロアリーレンであるか、R2、RP1、およびRP2は、反応基に結合した連結基を含んでよく;
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
各R13は、独立して、H、必要に応じて置換されたアルキルであるか、R13は、反応基に結合した連結基を含み;
R14は必要に応じて置換されたアルキルであり;
ここで、R1、R2、R13、RP1、およびRP2のうちの少なくとも1つは、反応基に結合した連結基を含む)のインテグリンターゲティングリガンド前駆体またはその薬学的に許容され得る塩を提供する。
多座αvβ6インテグリンリガンドおよび足場
反応基および保護された反応基。
カーゴ分子(RNAi剤が含まれる)
いくつかの実施形態では、1またはそれを超えるカーゴ分子(単数または複数)は、薬物動態(PK)モジュレーターとして作用することができるPEG部分を含み得るか、これからなり得る。いくつかの実施形態では、1またはそれを超えるカーゴ分子は、約20〜900のエチレンオキシド(CH2−CH2−O)単位(例えば、20〜850、20〜800、20〜750、20〜700、20〜650、20〜600、20〜550、20〜500、20〜450、20〜400、20〜350、20〜300、20〜250、20〜200、20〜150、20〜100、20〜75、20〜50、100〜850、100〜800、100〜750、100〜700、100〜650、100〜600、100〜550、100〜500、100〜450、100〜400、100〜350、100〜300、100〜250、100〜200、100〜150、200〜850、200〜800、200〜750、200〜700、200〜650、200〜600、200〜550、200〜500、200〜450、200〜400、200〜350、200〜300、200〜250、250〜900、250〜850、250〜800、250〜750、250〜700、250〜650、250〜600、250〜550、250〜500、250〜450、250〜400、250〜350、250〜300、300〜900、300〜850、300〜800、300〜750、300〜700、300〜650、300〜600、300〜550、300〜500、300〜450、300〜400、300〜350、350〜900、350〜850、350〜800、350〜750、350〜700、350〜650、350〜600、350〜550、350〜500、350〜450、350〜400、400〜900、400〜850、400〜800、400〜750、400〜700、400〜650、400〜600、400〜550、400〜500、400〜450、450〜900、450〜850、450〜800、450〜750、450〜700、450〜650、450〜600、450〜550、450〜500、500〜900、500〜850、500〜800、500〜750、500〜700、500〜650、500〜600、500〜550、550〜900、550〜850、550〜800、550〜750、550〜700、550〜650、550〜600、600〜900、600〜850、600〜800、600〜750、600〜700、600〜650、650〜900、650〜850、650〜800、650〜750、650〜700、700〜900、700〜850、700〜800、700〜750、750〜900、750〜850、750〜800、800〜900、850〜900、または850〜900のエチレンオキシド単位)を有するPEG部分を含み得る。いくつかの実施形態では、1またはそれを超えるカーゴ分子(単数または複数)は、およそ455エチレンオキシド単位(約20キロダルトン(kDa)の分子量)を有するPEG部分からなる。いくつかの実施形態では、PEG部分の分子量は約2キロダルトンである。いくつかの実施形態では、PEG部分の分子量は約20キロダルトンである。いくつかの実施形態では、PEG部分の分子量は約40キロダルトンである。本明細書中に記載のPEG部分は、直鎖または分枝鎖であり得る。PEG部分は、離散(単分散)または非離散(多分散)であり得る。PK増強カーゴ分子として使用するためのPEG部分は、商業的に購入することができる。いくつかの実施形態では、1またはそれを超えるカーゴ分子(単数または複数)には、PKモジュレーターまたはエンハンサーとして作用することができるPEG部分、および薬学的に活性な成分または化合物などの異なるカーゴ分子が含まれる。
医薬組成物
細胞、組織、および非ヒト生物
ターゲティング基、連結基、薬物動態(PK)モジュレーター、および送達ビヒクル
実施例1.αvβ6インテグリンリガンドの合成
構造物1b((14S,17S)−1−アジド−14−(5−((4−メチルピリジン−2−イル)アミノ)ペンタンアミド)−17−(4−(ナフタレン−1−イル)フェニル)−15−オキソ−3,6,9,12−テトラオキサ−16−アザノナデカン−19−酸)の合成。
構造物5b(3−(4−(2−(2−(2−アジドエトキシ)エトキシ)エトキシ)−3,5−ジクロロフェニル)−3−(2−(5−((4−メチルピリジン−2−イル)アミノ)ペンタンアミド)アセトアミド)プロパン酸)
構造物5.1b(3−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)−3,5−ジクロロフェニル)−3−(2−(5−((4−メチルピリジン−2−イル)アミノ)ペンタンアミド)アセトアミド)プロパン酸)
構造物5.2b(3−(4−((8−アジドオクチル)オキシ)−3,5−ジクロロフェニル)−3−(2−(5−((4−メチルピリジン−2−イル)アミノ)ペンタンアミド)アセトアミド)プロパン酸)
構造物6b、6.1b、6.2b、6.3b、および6.4bの合成。
構造物6b((S)−3−(4−(4−(2−(2−(2−アジドエトキシ)エトキシ)エトキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)
構造物6.1b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)
構造物6.2b((S)−3−(4−(4−((8−アジドオクチル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)
構造物6.3b((S)−3−(4−(4−((20−アジド−3,6,9,12,15,18−ヘキサオキサイコシル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)
構造物6.4b((S)−3−(4−(4−((35−アジド−3,6,9,12,15,18,21,24,27,30,33−ウンデカオキサペンタトリアコンチル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)
構造物7b((R)−3−(4−(4−(2−(2−(2−アジドエトキシ)エトキシ)エトキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物8b((S)−3−(4−(7−(2−(2−(2−アジドエトキシ)エトキシ)エトキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物9b((14S,17R)−1−アジド−14−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)−17−(4−(ナフタレン−1−イル)フェニル)−15−オキソ−3,6,9,12−テトラオキサ−16−アザノナデカン−19−酸)の合成。
構造物10b((S)−3−(4−(5−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物11b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−1−(4−((4−メチルピリジン−2−イル)アミノ)ブタノイル)ピロリジン−2−カルボキサミド)プロパン酸)の合成。
構造物12b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ベンゾ[d]オキサゾール−7−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物13b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)−5,6,7,8−テトラヒドロナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物14b((S)−3−(4’−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)−2’−(トリフルオロメトキシ)−[1,1’−ビフェニル]−4−イル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物15b((S)−3−(3−(5−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物16b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((R)−1−(4−((4−メチルピリジン−2−イル)アミノ)ブタノイル)ピロリジン−2−カルボキサミド)プロパン酸)の合成。
構造物17b((S)−3−(4−(7−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ベンゾ[b]チオフェン−4−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物18b((S)−3−(4−(6−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−2−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物19b((S)−3−(3−(6−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−2−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物20b((S)−3−(3−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物22b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)プロパンアミド)プロパン酸)の合成。
構造物23b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−3−メチル−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)ブタンアミド)プロパン酸)の合成。
構造物24b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)−3−フェニルプロパンアミド)プロパン酸)の合成。
構造物25b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−3−(ベンジルオキシ)−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)プロパンアミド)プロパン酸)の合成。
構造物27b((S)−3−(3−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)−3,5−ジメチル−1H−ピラゾール−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物29b((S)−3−(4−(3−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−(2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)アセトアミド)プロパン酸)の合成。
構造物30b((S)−N−(1−アジド−21−(4−(ナフタレン−1−イル)フェニル)−19,23−ジオキソ−3,6,9,12,15−ペンタオキサ−18,22−ジアザテトラコサン−24−イル)−4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)の合成。
構造物31b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−3−ヒドロキシ−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)プロパンアミド)プロパン酸)の合成。
構造物32b((S)−4−(((S)−1−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−2−カルボキシエチル)アミノ)−3−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)−4−オキソブタン酸)の合成。
構造物33b((S)−3−((S)−6−アミノ−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)ヘキサンアミド)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)プロパン酸)の合成。
構造物34b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((S)−4−メチル−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)ペンタンアミド)プロパン酸)の合成。
構造物35b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((2S,3R)−3−ヒドロキシ−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)ブタンアミド)プロパン酸)の合成。
構造物36b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((2S,3S)−3−メチル−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)ペンタンアミド)プロパン酸)の合成。
構造物37b((S)−3−(4−(4−((14−アジド−3,6,9,12−テトラオキサテトラデシル)オキシ)ナフタレン−1−イル)フェニル)−3−((R)−3−メチル−2−(4−((4−メチルピリジン−2−イル)アミノ)ブタンアミド)ブタンアミド)プロパン酸)の合成。
実施例2.三座αvβ6インテグリンリガンドの合成およびαvβ6インテグリンリガンドのカーゴ分子(RNAi剤)への結合。
本明細書中の一定の実施形態に示したRNAi剤に接続して使用する場合、トリアルキン含有ホスホルアミダイトを無水ジクロロメタンまたは無水アセトニトリル(50mM)に溶解し、一方で、全ての他のアミダイトを無水アセトニトリル(50mM)に溶解し、モレキュラーシーブ(3Å)を添加した。5−ベンジルチオ−1H−テトラゾール(BTT、250mMのアセトニトリル溶液)または5−エチルチオ−1H−テトラゾール(ETT、250mMのアセトニトリル溶液)を、アクチベーター溶液として使用した。カップリング時間は、10分間(RNA)、90秒間(2’O−Me)、および60秒間(2’F)であった。ホスホロチオアート連結を導入するために、100mMの3−フェニル1,2,4−ジチアゾリン−5−オン(POS、PolyOrg,Inc.,Leominster,MA,USAから入手)を含む無水アセトニトリルの溶液を使用した。
実施例3.αvβ6インテグリンリガンド結合活性。
実施例4.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo気管内投与。
センス鎖配列(5’→3’):
(NH2−C6)sgscugugcaAfCfCfagaacaaauas(invAb)(配列番号1)
アンチセンス鎖配列(5’→3’)
cPrpusAfsusUfuGfuUfcUfgGfuUfgCfaCfaGfsc(配列番号2)
ここで、(invAb)は、反転(3’−3’連結)脱塩基デオキシリボヌクレオチドを表し;sは、ホスホロチオアート連結を表し;a、c、g、およびuは、それぞれ、2’−O−メチルアデノシン、2’−O−メチルシチジン、2’−O−メチルグアノシン、または2’−O−メチルウリジンを表し;Af、Cf、Gf、およびUfは、それぞれ、2’−フルオロアデノシン、2’−フルオロシチジン、2’−フルオログアノシン、または2’−フルオロウリジンを表し;cPrpuは、5’−シクロプロピルホスホナート−2’−O−メチルウリジンを表し(例えば、表Aを参照のこと);(NH2−C6)は、必要に応じてターゲティングリガンド結合を容易にするためのC6末端アミンを表す(例えば、表Aを参照のこと)。
(1)5%デキストロースを含む水性ビヒクル(D5W);
(2)3.0mg/kgの、5%デキストロース水溶液(d5w)中に処方されたリガンドを含まないα−ENaC RNAi剤(AD04835)(「ネイキッドRNAi剤」);または
(3)3.0mg/kgの、d5w中に処方された構造物1の三座αvβ6インテグリンリガンドに結合されたα−ENaC RNAi剤(AD04835)。
実施例5.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo口腔咽頭吸引投与。
実施例6.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo口腔咽頭吸引投与。
AD05347:
センス鎖配列(5’→3’):
(NH2−C6)cscugugcaAfCfCfagaacaaauas(invAb)(配列番号3)
アンチセンス鎖配列(5’→3’)
cPrpusAfsusUfuGfuUfcUfgGfuUfgCfaCfaGfsc(配列番号2)、および
AD05453:
センス鎖配列(5’→3’):
(NH2−C6)cscugugcaAfCfCfagaacaaauas(invAb)(配列番号3)
アンチセンス鎖配列(5’→3’)
usAfsusUfuGfuUfcUfgGfuUfgCfaCfaGfsg(配列番号4)、
ここで、(invAb)は、反転(3’−3’連結)脱塩基デオキシリボヌクレオチドを表し;sは、ホスホロチオアート連結を表し;a、c、g、およびuは、それぞれ、2’−O−メチルアデノシン、2’−O−メチルシチジン、2’−O−メチルグアノシン、または2’−O−メチルウリジンを表し;Af、Cf、Gf、およびUfは、それぞれ、2’−フルオロアデノシン、2’−フルオロシチジン、2’−フルオログアノシン、または2’−フルオロウリジンを表し;cPrpuは、5’−シクロプロピルホスホナート−2’−O−メチルウリジンを表し(例えば、表Aを参照のこと);(NH2−C6)は、必要に応じてターゲティングリガンド結合を容易にするためのC6末端アミンを表す(例えば、表Aを参照のこと)。
実施例7.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo口腔咽頭吸引投与。
実施例8.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo気管内投与
実施例9.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo気管内投与
群1中の五(5)匹のラットに服薬させ(n=5)、各群2および3中の四(4)匹のラットに服薬させた(n=4)。研究9日目にラットを屠殺し、採取および均一化後に両肺から全てのRNAを単離した。α−ENaC(SCNN1A)mRNA発現を、プローブベースの定量PCRによって定量し、GAPDH発現に対して正規化し、ビヒクル対照群に対する割合として示した(幾何平均、+/−95%信頼区間)。
実施例10.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo気管内投与。
実施例11.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo口腔咽頭吸引投与。
実施例12.さらなるαvβ6インテグリンリガンド結合活性。
実施例13.ラットにおけるαvβ6インテグリンリガンドに結合したα−ENaCを標的にするRNAi剤のin vivo口腔咽頭吸引投与。
Claims (36)
- αvβ6インテグリンリガンドであって、以下の構造物:
nは0〜7の整数であり;
JはC−HまたはNであり;
Zは、OR13、N(R13)2、またはSR13であり;
R1は、H、必要に応じて置換されたC1〜C6アルキル、OH、COOH、CON(R5)2、OR6であるか、R1は、カーゴ分子を含み、ここで、各R5は、独立して、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2、RP1、およびRP2は、各々独立して、H、ハロ、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、または必要に応じて置換されたヘテロアリーレンであるか、R2、RP1、およびRP2は、カーゴ分子を含んでよく;
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
各R13は、独立して、H、必要に応じて置換されたアルキルであるか、R13は、カーゴ分子を含み;
R14は必要に応じて置換されたアルキルであり;
ここで、R1、R2、R13、RP1、およびRP2のうちの少なくとも1つは、カーゴ分子を含む)を含むαvβ6インテグリンリガンドまたはその薬学的に許容され得る塩。 - αvβ6インテグリンリガンドであって、以下の構造物:
nは、0〜7の整数であり(すなわち、nは、0、1、2、3、4、5、6、または7である);
JはC−HまたはNであり;
R1は、H、C1〜C6アルキル、CH(R3)(R4)、OH、COOH、CH2CH2CH2NH2、CONHR5、OR6であるか、R1は、カーゴ分子を含み、ここで、R3は、HまたはC1〜C6アルキルであり、R4は、H、C1〜C6アルキルであり、R5は、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2は、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、必要に応じて置換されたヘテロアリーレンであるか、R2はカーゴ分子を含み、
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
R13は、Hまたは必要に応じて置換されたアルキルであり;
R14は必要に応じて置換されたアルキルであり;
ここで、R1またはR2のうちの少なくとも1つはカーゴ分子を含む)を含むαvβ6インテグリンリガンドまたはその薬学的に許容され得る塩。 - 以下の構造物:
nは、1〜7の整数であり(すなわち、nは、1、2、3、4、5、6、または7である);
R7は、1またはそれを超えるカーゴ分子を含み;
R8は、2、3、4、5、6、7、8、9、または10個の炭素原子を有する1またはそれを超える必要に応じて置換された2価の環状部分(シクロアルキル(例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、またはシクロヘプチル)、シクロアルケニル(例えば、シクロペンテニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、またはシクロヘプテニル)、アリール(例えば、フェニル)、ヘテロアリール(例えば、ピリジル、ピリミジニル、ピリダジニル、ピロール、ピラゾール、イミダゾール、チオフェン、ベンゾチオフェン、チアゾール、ベンゾチアゾール、フラン、オキサゾール、イソキサゾール、ベンゾフラン、インドール、インダゾール、ベンズイミダゾール、オキサジアゾール、1,2,3−トリアゾール、1,2,4−トリアゾール、テトラゾール、キノリニル、イソキノリニル、またはキノキサリニル)、またはヘテロシクリル(例えば、テトラヒドロフラン、テトラヒドロピラン、ピペリジン、ピロリジン、ジオキサン、またはジオキソラン)など)である)を含む、請求項1に記載のαvβ6インテグリンリガンドまたはその薬学的に許容され得る塩。 - 以下の構造物:
nは、1〜7の整数であり(すなわち、nは、1、2、3、4、5、6、または7である);
R8は、1またはそれを超えるカーゴ分子を含む)を含む、請求項1に記載のαvβ6インテグリンリガンドまたはその薬学的に許容され得る塩。 - nが3である、請求項1〜3のいずれか1項に記載のαvβ6インテグリンリガンド。
- nが4である、請求項1〜3のいずれか1項に記載のαvβ6インテグリンリガンド。
- 以下:
- 以下:
- 前記カーゴ分子が、医薬品有効成分またはプロドラッグである、請求項1〜8のいずれか1項に記載のαvβ6インテグリンリガンド。
- 前記カーゴ分子が、小分子、抗体、抗体断片、免疫グロブリン、モノクローナル抗体、標識もしくはマーカー、脂質、天然もしくは修飾された核酸、天然もしくは修飾された核酸オリゴヌクレオチド、天然もしくは修飾された核酸ポリヌクレオチド、ペプチド、アプタマー、ポリマー、ポリアミン、タンパク質、毒素、ビタミン、ポリエチレングリコール、ハプテン、ジゴキシゲニン、ビオチン、放射性の原子もしくは分子、またはフルオロフォアを含む、請求項1〜8のいずれか1項に記載のαvβ6インテグリンリガンド。
- 前記カーゴ分子がRNAi剤を含む、請求項1〜8のいずれか1項に記載のαvβ6インテグリンリガンド。
- 2〜20エチレンオキシド単位を有するポリエチレングリコールリンカーをさらに含む、請求項1〜11のいずれか1項に記載のαvβ6インテグリンリガンド。
- 前記カーゴ分子に結合している、請求項1〜12のいずれか1項に記載のαvβ6インテグリンリガンド、連結基、および足場を含む構造物。
- 単座形態の前記αvβ6インテグリンリガンドを含む、請求項13に記載の構造物。
- 二座形態の前記αvβ6インテグリンリガンドを含む、請求項13に記載の構造物。
- 三座形態の前記αvβ6インテグリンリガンドを含む、請求項13に記載の構造物。
- 四座形態の前記αvβ6インテグリンリガンドを含む、請求項13に記載の構造物。
- 前記足場が、以下の式:
- 以下の構造物:
nは0〜7の整数であり;
JはC−HまたはNであり;
Zは、OR13、N(R13)2、またはSR13であり;
R1は、H、必要に応じて置換されたC1〜C6アルキル、OH、COOH、CON(R5)2、OR6であるか、R1は、反応基に結合した連結基を含み、ここで、各R5は、独立して、HまたはC1〜C6アルキルであり、R6は、HまたはC1〜C6アルキルであり;
R2、RP1、およびRP2は、各々独立して、H、必要に応じて置換されたシクロアルキレン、必要に応じて置換されたアリーレン、必要に応じて置換されたヘテロシクロアルキレン、または必要に応じて置換されたヘテロアリーレンであるか、R2、RP1、およびRP2は、反応基に結合した連結基を含んでよく;
R10は、Hまたは必要に応じて置換されたアルキルであり;
R11は、Hまたは必要に応じて置換されたアルキルであるか、R11およびR1は、これらに付着している原子と共に、必要に応じて置換されたヘテロ環を形成し;
R12は、Hまたは必要に応じて置換されたアルキルであり;
各R13は、独立して、H、必要に応じて置換されたアルキルであるか、R13は、反応基に結合した連結基を含み;
R14は必要に応じて置換されたアルキルであり;
ここで、R1、R2、R13、RP1、およびRP2のうちの少なくとも1つは、反応基に結合した連結基を含む)を含むαvβ6インテグリンリガンド前駆体またはその薬学的に許容され得る塩。 - 前記連結基がPEGリンカーである、請求項19に記載のαvβ6インテグリンリガンド前駆体。
- 前記PEGリンカーが2〜20PEG単位を含む、請求項19に記載のαvβ6インテグリンリガンド前駆体。
- 前記反応基がアジドである、請求項19に記載のαvβ6インテグリンリガンド前駆体。
- 前記反応基に結合した連結基が、以下の構造物:
- 以下:
- 請求項1〜12のいずれかに記載のαvβ6インテグリンリガンドまたは請求項13〜18のいずれかに記載の構造物、および薬学的に許容され得る賦形剤を含む組成物。
- 前記αvβ6インテグリンリガンドが、上皮細胞中の標的遺伝子の発現を阻害することができるオリゴヌクレオチド系化合物に結合している、請求項25に記載の組成物。
- 前記αvβ6インテグリンリガンドが、上皮細胞中の標的遺伝子の発現を阻害することができるRNAi剤に結合している、請求項25に記載の組成物。
- 前記αvβ6インテグリンリガンドが、細気管支上皮細胞中の標的遺伝子の発現を阻害することができるRNAi剤に結合している、請求項25に記載の組成物。
- 1またはそれを超えるカーゴ分子を細胞に送達させる方法であって、請求項1〜12のいずれかに記載のαvβ6インテグリンリガンドまたは請求項13〜18のいずれかに記載の構造物を前記細胞に投与する工程を含む、方法。
- 1またはそれを超えるカーゴ分子を被験体の細胞または組織にin vivoで送達させる方法であって、請求項1〜12のいずれかに記載のαvβ6インテグリンリガンド、請求項13〜18のいずれかに記載の構造物、または請求項19〜22のいずれかに記載の組成物を前記被験体に投与する工程を含む、方法。
- 前記細胞が、以下:I型およびII型の肺胞上皮細胞、杯細胞、分泌上皮細胞、線毛上皮細胞、角膜および結膜の上皮細胞、真皮上皮細胞、胆管細胞、腸細胞、管上皮細胞、腺上皮細胞、および上皮性腫瘍(癌腫)からなる群から選択される、請求項29または30に記載の方法。
- 前記1またはそれを超えるカーゴ分子が、オリゴヌクレオチド系化合物を含む、請求項29または30に記載の方法。
- 前記オリゴヌクレオチド系化合物がRNAi剤である、請求項32に記載の方法。
- in vivoで細胞中の標的遺伝子の発現を阻害する方法であって、有効量の、請求項1〜12のいずれかに記載のαvβ6インテグリンリガンドに結合したオリゴヌクレオチド系化合物を含む組成物を被験体に投与する工程を含む、方法。
- 前記細胞が、以下:I型およびII型の肺胞上皮細胞、杯細胞、分泌上皮細胞、線毛上皮細胞、角膜および結膜の上皮細胞、真皮上皮細胞、胆管細胞、腸細胞、管上皮細胞、腺上皮細胞、および上皮性腫瘍(癌腫)からなる群から選択される、請求項34に記載の方法。
- 前記オリゴヌクレオチド系化合物がRNAi剤である、請求項34または35に記載の方法。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002537287A (ja) * | 1999-02-20 | 2002-11-05 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | β−アラニン誘導体 |
WO2008006102A2 (en) * | 2006-07-07 | 2008-01-10 | The Scripps Research Institute | Use of retro-aldol reaction to generate reactive vinyl ketone for attachment to anitibody molecules by michael addition reaction for use in immunostaining and immunotargeting |
JP2013506709A (ja) * | 2009-10-06 | 2013-02-28 | イミュノジェン・インコーポレーテッド | 有効なコンジュゲートおよび親水性リンカー |
JP2013514326A (ja) * | 2009-12-17 | 2013-04-25 | ジーイー・ヘルスケア・リミテッド | 標識インテグリン結合剤 |
WO2015179823A2 (en) * | 2014-05-23 | 2015-11-26 | The California Institute For Biomedical Research | Lung localized inhibitors of alpha(v)beta 6 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
DE19831710A1 (de) | 1998-07-15 | 2000-01-20 | Merck Patent Gmbh | Diacylhydrazinderivate |
DE19929410A1 (de) | 1999-06-26 | 2000-12-28 | Merck Patent Gmbh | Inhibitoren des Integrins avß6 |
DE10028402A1 (de) | 2000-06-13 | 2001-12-20 | Merck Patent Gmbh | Pyridin-2-yl-aminoalkycarbonylglycyl-beta-alanin und Derivate |
WO2006020768A2 (en) | 2004-08-10 | 2006-02-23 | Alnylam Pharmaceuticals, Inc. | Chemically modified oligonucleotides |
GB0520068D0 (en) | 2005-10-03 | 2005-11-09 | Cancer Res Technology | av peptide ligand |
US20110003858A1 (en) | 2006-09-04 | 2011-01-06 | Bergstroem Lena | Multimeric heterocyclic compounds useful as neutrophil elastase inhibitors |
AR066984A1 (es) | 2007-06-15 | 2009-09-23 | Novartis Ag | Inhibicion de la expresion de la subunidad alfa del canal epitelial de sodio (enac) por medio de arni (arn de interferencia) |
EP2221334B1 (en) | 2007-11-28 | 2016-12-28 | FUJIFILM Corporation | Method for chemically modifying biopolymer and polypeptide |
US9884070B2 (en) * | 2008-04-21 | 2018-02-06 | Lawrence Livermore National Security, Llc | Selective high-affinity polydentate ligands and methods of making such |
US9161948B2 (en) * | 2011-05-05 | 2015-10-20 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
CN104220094A (zh) | 2012-02-17 | 2014-12-17 | 西雅图基因公司 | 针对整联蛋白αvβ6的抗体和使用该抗体治疗癌症 |
JP2014029990A (ja) | 2012-06-29 | 2014-02-13 | Sharp Corp | 窒化物半導体装置の電極構造およびその製造方法並びに窒化物半導体電界効果トランジスタ |
EP2913064A1 (en) * | 2014-02-26 | 2015-09-02 | celares GmbH | Branched drug-linker conjugates for the coupling to biological targeting molecules |
ES2930029T3 (es) | 2014-04-15 | 2022-12-05 | Univ California | Péptidos de unión a integrina pegilados biterminales y métodos para su uso |
JP6773677B2 (ja) | 2015-03-17 | 2020-10-21 | アローヘッド ファーマシューティカルズ インコーポレイテッド | 改善されたジスルフィド含有アルキン連結剤 |
CN108064156B (zh) * | 2015-05-29 | 2022-02-01 | 箭头药业股份有限公司 | 抑制Hif2α基因表达的组合物及方法 |
JOP20170161A1 (ar) | 2016-08-04 | 2019-01-30 | Arrowhead Pharmaceuticals Inc | عوامل RNAi للعدوى بفيروس التهاب الكبد ب |
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-
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2023
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002537287A (ja) * | 1999-02-20 | 2002-11-05 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | β−アラニン誘導体 |
WO2008006102A2 (en) * | 2006-07-07 | 2008-01-10 | The Scripps Research Institute | Use of retro-aldol reaction to generate reactive vinyl ketone for attachment to anitibody molecules by michael addition reaction for use in immunostaining and immunotargeting |
JP2013506709A (ja) * | 2009-10-06 | 2013-02-28 | イミュノジェン・インコーポレーテッド | 有効なコンジュゲートおよび親水性リンカー |
JP2013514326A (ja) * | 2009-12-17 | 2013-04-25 | ジーイー・ヘルスケア・リミテッド | 標識インテグリン結合剤 |
WO2015179823A2 (en) * | 2014-05-23 | 2015-11-26 | The California Institute For Biomedical Research | Lung localized inhibitors of alpha(v)beta 6 |
Non-Patent Citations (4)
Title |
---|
GOSWAMI R. K. ET AL.: "Chemically Programmed Antibodies Targeting Multiple Alpha(v) Integrins and Their Effects on Tumor-Re", BIOCONJUGATE CHEMISTRY, vol. 22, JPN6022041533, 20 July 2011 (2011-07-20), pages 1535 - 1544, ISSN: 0005069000 * |
REGISTRY(STN)[ONLINE], JPN7022004668, 2 August 2002 (2002-08-02), ISSN: 0005069002 * |
REGISTRY(STN)[ONLINE], JPN7022004669, 16 August 2002 (2002-08-16), ISSN: 0005069003 * |
REGISTRY(STN)[ONLINE], JPN7022004670, 2 August 2002 (2002-08-02), ISSN: 0005069001 * |
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