JP2016501851A - 心不全治療用の合成鎖状アペリン模倣物 - Google Patents
心不全治療用の合成鎖状アペリン模倣物 Download PDFInfo
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- JP2016501851A JP2016501851A JP2015543111A JP2015543111A JP2016501851A JP 2016501851 A JP2016501851 A JP 2016501851A JP 2015543111 A JP2015543111 A JP 2015543111A JP 2015543111 A JP2015543111 A JP 2015543111A JP 2016501851 A JP2016501851 A JP 2016501851A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
Description
X1は、ポリペプチドのN末端であり、存在しない、Q、A、またはpEであり、
X2は、Rまたはrであり、
X3は、Pまたは4−PhPであり、
X5は、L、Cha、D−L、F、Y、Y(Bzl)、3,4−Cl2−F、またはNaIであり、
X6は、D−アミノ酸、S、またはAであり、
X7は、D−アミノ酸、L、H、またはAibであり、X6およびX7の少なくとも一方は、D−アミノ酸またはAibであり、
X8は、K、k、Q、またはEであり、
X9は、GまたはDであり、
X10は、Pまたはピペコリン酸であり、
X11は、D−Nle、Nle、f、またはD−Nvaであり、
X12は、不在、P、またはD−アミノ酸であり、
X13は、C末端であり、存在しない、F、またはD−アミノ酸であり、X11、X12、およびX13の少なくとも1つは、D−アミノ酸であり、
Nleは、L−ノルロイシンであり、
D−Nleは、D−ノルロイシンであり、
Nalは、L−(ナフチル)アラニンであり、
D−Nvaは、D−ノルバリンであり、
Aibは、α−アミノイソ酪酸であり、
Chaは、(S)−β−シクロヘキシルアラニンであり、
D−Ticは、D−1,2,3,4−テトラヒドロイソキノリン−3−カルボン酸であり、
pEは、L−ピログルタミン酸であり、
3,4−Cl2−Fは、(S)−3,4−ジクロロフェニルアラニンであり、
Yは、L−チロシンであり、
Y(Bzl)は、L−ベンジル−チロシンである]
またはこのポリペプチドのアミド、エステル、もしくは塩、またはこれらと実質的に同等なポリペプチドを提供する。
a. 式I〜IVのいずれか1つのペプチドまたはポリペプチド、
b. 半減期延長性部分
を含み、
前記ペプチドまたはポリペプチドと前記半減期は、場合によりリンカーを介して、共有結合によって連結している、
バイオコンジュゲートまたはその多量体を提供する。
本出願を説明する目的のために、別段指定しない限り、また相応しい場合は常に、以下の定義が適用され、単数形で使用する用語は、複数形の語も包含し、逆の場合も同様である。
本発明の種々の実施形態を本明細書に記載する。各実施形態において明記する特色を、明記された他の特色と組み合わせて、別の実施形態としてもよいことは、認識されるであろう。
X1は、ポリペプチドのN末端であり、存在しない、Q、A、またはpEであり、
X2は、Rまたはrであり、
X3は、Pまたは4−PhPであり、
X5は、L、Cha、D−L、F、Y、Y(Bzl)、3,4−Cl2−F、またはNaIであり、
X6は、D−アミノ酸、S、またはAであり、
X7は、D−アミノ酸、L、H、またはAibであり、X6およびX7の少なくとも一方は、D−アミノ酸またはAibであり、
X8は、K、k、Q、またはEであり、
X9は、GまたはDであり、
X10は、Pまたはピペコリン酸であり、
X11は、D−Nle、Nle、f、またはD−Nvaであり、
X12は、存在しない、P、またはD−アミノ酸であり、
X13は、C末端であり、存在しない、F、またはD−アミノ酸であり、X11、X12、およびX13の少なくとも1つは、D−アミノ酸であり、
Nleは、L−ノルロイシンであり、
D−Nleは、D−ノルロイシンであり、
Nalは、L−(ナフチル)アラニンであり、
D−Nvaは、D−ノルバリンであり、
Aibは、α−アミノイソ酪酸であり、
Chaは、(S)−β−シクロヘキシルアラニンであり、
D−Ticは、D−1,2,3,4−テトラヒドロイソキノリン−3−カルボン酸であり、
pEは、L−ピログルタミン酸であり、
3,4−Cl2−Fは、(S)−3,4−ジクロロフェニルアラニンであり、
Yは、L−チロシンであり、
Y(Bzl)は、L−ベンジル−チロシンである]
またはこのポリペプチドのアミド、エステル、もしくは塩、またはこれらと実質的に同等なポリペプチドを提供する。
X1は、ポリペプチドのN末端であり、存在しない、Q、A、またはpEであり、
X2は、Rまたはrであり、
X3は、Pまたは4−PhPであり、
X5は、L、Cha、D−L、F、Y、Y(Bzl)、3,4−Cl2−F、または2−NaIであり、
X6は、D−アミノ酸またはSであり、
X7は、D−アミノ酸、H、またはAibであり、X6およびX7の少なくとも一方は、D−アミノ酸またはAibであり、
X8は、Kまたはkであり、
X10は、Pまたはピペコリン酸であり、
X11は、D−NleまたはNleであり、
X12は、存在しない、P、またはD−アミノ酸であり、
X13は、C末端であり、存在しない、F、またはD−アミノ酸であり、X11、X12、およびX13の少なくとも1つは、D−アミノ酸である]
またはこのポリペプチドのアミド、エステル、もしくは塩、またはこれらと実質的に同等なポリペプチドを提供する。
pは、1〜4の整数であり、
mは、1〜12の整数であり、
ラウロイル(O2Oc)pは、C11H23C(O)[NH−(CH2)2−O−(CH2)2−O−CH2−C(O)]p−であり、
ミリストイル(O2Oc)pは、C13H27C(O)[NH−(CH2)2−O−(CH2)2−O−CH2−C(O)]p−であり、
パルミトイル(O2Oc)pは、C15H31C(O)[NH−(CH2)2−O−(CH2)2−O−CH2−C(O)]p−である、式I、IA、II、IIIまたはIVのいずれか1つ、または上述した他のいずれかのクラスおよびサブクラスのいずれかに従うペプチドおよびポリペプチド、またはそのアミド、エステル、もしくは塩に関する。この実施形態の特定の一態様では、Rは、アセチル、ベンゾイル、フェナシル、スクシニル、オクタノイル、4−フェニルブタノイル、4−Cl−Ph−(CH2)3C(O)−、またはPh−CH2CH2NHC(O)−である。N末端アミドの例は、参照により本明細書に援用される、2012年1月27日出願の米国仮出願第61/591,557号(代理人整理番号PAT054961−US−PSP)に記載されている。
a. 前述の実施形態のいずれかに従う、式I、IA、II、III、もしくはIVのペプチドもしくはポリペプチド、そのアミド、塩、またはエステル、
b. 半減期延長性部分
を含み、
前記ペプチドまたはポリペプチドと、前記半減期延長性部分は、場合によりリンカーを介して、共有結合によって連結している、
バイオコンジュゲートまたはその多量体に関する。
本発明の半減期延長性部分は、ペプチドまたはポリペプチド類似体に共有結合によって付着、連結、またはコンジュゲートしていてよい。半減期延長性部分は、たとえば、ポリエチレングリコール(PEG)などのポリマー、コレステロール基、炭水化物、もしくはオリゴ糖、またはサルベージ受容体に結合するいずれかの天然もしくは合成タンパク質、ポリペプチド、もしくはペプチドでよい。半減期延長性部分は、血清半減期の長い血漿タンパク質(アルブミンおよび免疫グロブリン)に、場合によりリンカーを介して、共有結合によって連結していることが好ましい。たとえば、半減期延長性部分は、IgG定常ドメインもしくはその断片(たとえば、Fc領域)、ヒト血清アルブミン(HSA)、またはアルブミン結合性ポリペプチドである。バイオコンジュゲートの半減期延長性部分の部分は、ヒト血清アルブミンであることが好ましい。
リンカー基は、任意選択である。存在するとき、リンカー基は、主としてスペーサーとして働くので、その化学構造は肝要でない。
本発明のペプチドおよびポリペプチドは、ペプチド合成のための、それ自体が知られている手順によって生成することができる。ペプチド合成の方法は、固相合成および液相合成のいずれかのものでよい。すなわち、問題のペプチドおよびポリペプチドは、タンパク質を構成し得る部分的なペプチドまたはアミノ酸をその残部と縮合させ、生成物が保護基を有するとき、保護基を外し、その後、所望のペプチドを製造することができる。縮合および脱保護の既知の方法としては、以下の文献(1)〜(5)に記載の手順が挙げられる。
(1)M. Bodanszky and M. A. Ondetti, Peptide Synthesis, Interscience Publishers, New York, 1966、
(2)Schroeder and Luebke, The Peptide, Academic Press, New York, 1965、
(3)Nobuo Izumiya et al. Fundamentals and Experiments in Peptide Synthesis, Maruzen, 1975、
(4)Haruaki Yajima and Shumpei Sakakibara, Biochemical Experiment Series 1, Protein Chemistry IV, 205, 1977、および
(5)Haruaki Yajima (ed.), Development of Drugs-Continued, 14, Peptide Synthesis, Hirokawa Shoten
本発明の一実施形態では、式I〜IVのいずれか1つに従うペプチドまたはポリペプチドを、アルブミンのシステイン34のチオール官能基にコンジュゲートさせる(化学的/共有結合性に付着させる)。この実施形態の一実施形態では、アルブミン−ペプチドは、アルブミンがペプチドのN末端にコンジュゲート(化学的に連結)している、バイオコンジュゲートを指す。さらに別の実施形態では、アルブミン−ペプチドは、アルブミンがペプチドのC末端にコンジュゲート(化学的に連結)している、バイオコンジュゲートを指す。
スキーム4および5は、APJアゴニストペプチド、または式I〜IVのいずれか1つに従うペプチドと、Fcドメインやアルブミンなどの半減期延長性部分とをコンジュゲートさせる化学反応を説明するものである。
本発明のポリペプチドまたはバイオコンジュゲート、またはそのアミド、塩のエステルは、皮下、筋肉内、静脈内、腹腔内、吸入、鼻腔内、経口などを始めとする様々な手段のいずれかにおいて投与することができる。本発明の特に好ましい実施形態では、本発明のポリペプチドまたはバイオコンジュゲート、またはそのアミド、エステル、もしくは塩の連続的な静脈内投与を用いる。本発明におけるポリペプチドは、ボーラスとして、または一定期間にわたる連続注入として投与することができる。移植可能なポンプを使用してもよい。本発明のある特定の実施形態では、断続的または連続的なポリペプチドもしくはバイオコンジュゲート投与を、1日〜数日間(たとえば、2〜3日間以上)またはより長期間、たとえば、数週間、数か月、もしくは数年間継続する。一部の実施形態では、断続的または連続的なポリペプチド投与を少なくとも約3日間施す。別の実施形態では、断続的または連続的なポリペプチド投与を少なくとも約1週間施す。他の実施形態では、断続的または連続的なポリペプチドもしくはバイオコンジュゲート投与を少なくとも約2週間施す。投与中または複数回の投与の合間に、特定の閾値を上回る平均血漿ポリペプチド濃度を維持することが望ましい場合もある。望ましい濃度は、たとえば、対象の生理的状態、疾患重症度などに基づき決定することができる。そのような望ましい値(複数可)は、標準の臨床試験を実施して割り出すことができる。代わりに、ペプチドおよびそのコンジュゲートは、FcRn機序によって、経口的に送達することができるはずである(Nat Rev Immunol. 7(9), 715-25, 2007、Nat Commun. 3;3:610, 2012、Am J Physiol Gastrointest Liver Physiol 304: G262-G270, 2013)。
アペリンファミリーのペプチドは、Gタンパク質共役型APJ受容体の、知られている唯一の天然リガンドファミリーである。アペリン遺伝子は、77アミノ酸のポリペプチドをコードし、このポリペプチドがプロセシングを受けて、生物学的活性型のアペリンペプチド、たとえば、アペリン−36、アペリン−17、アペリン−16、アペリン−13、アペリン−12、およびピログルタミン酸修飾型のアペリン−13(Pyr1−アペリン−13)になる。これらアペリンペプチドのいずれでも1種が、APJ受容体に結合すると、GiおよびGqタンパク質を介してシグナルを伝達する。心筋細胞では、GiまたはGqとの共役によって、細胞内pHが変化し、PLCが活性化され、IP3が産生され、それにより筋フィラメントのカルシウム感受性が増強され、最終的に心収縮性が増大する。Gi共役により、活性化型Gs、アデニリルシクラーゼ、およびcAMPの産生が抑制され、pAktレベルが上昇して、心臓保護につながる。血管内皮細胞では、Giを介したAPJ活性化、pAKTによって、一酸化窒素(NO)産生が増大し、これにより平滑筋弛緩が増進される結果、全体として血管が拡張する。
384ウェルフォーマットにおいて、25ul成長培地に、Chem−5 APJ安定細胞(Millipore#HTS068C)を10,000細胞/ウェルで播き、次いで、37℃の組織培養インキュベーターにおいて24時間成長させた。アッセイの1時間前に、2.5mMのプロベネシドを含有する25ul/ウェルのFLIPR Calcium 4色素(Molecular Devices R8142)を加え、37℃の組織培養インキュベーターにおいて細胞を1時間インキュベートした。ペプチドをHBSS、HEPES、および0.1%BSA緩衝液に可溶化し、三通りに50uMから5pMまで10倍ずつ連続希釈した。FLIPR Tetraを使用して、色素を有する細胞にペプチドを加えた(1:5、10uM〜1pMの範囲の最終ペプチド濃度にする)。細胞の内側のFLIPR色素は、カルシウムに結合後に蛍光を発光し、細胞の外側からの蛍光は遮蔽された。FLIPR Tetraにおいて470〜495の励起波長および515〜575の発光波長を使用して、蛍光を測定した。読取りは、ペプチドを加える10秒前に開始して、合計3分間行った。最大−最小値を算出し、各ペプチド濃度に対してプロットし、GraphPad prismソフトウェアを使用して、ペプチドによるカルシウムフラックス刺激について、曲線変曲点におけるEC50値を算出した。
材料:
作業溶液:1mg/mLの試験物をMilli−Q水中に調製する。
抽出溶液:0.1%のギ酸および400ng/mLのグリブリドを含有するメタノール:アセトニトリル:水(1:1:1)
血漿:Bioreclamation LLC(ニューヨーク州Liverpool)から購入した雄のSprague−Dawleyラット血漿(ヘパリンナトリウム添加)
全血:Bioreclamation LLC(ニューヨーク州Liverpool)から購入した雄Sprague Dawley全血(ヘパリンナトリウム添加)
肺ホモジネート:Bioreclamation LLC(ニューヨーク州Liverpool)から雄のSprague Dawleyラットの肺を購入した。肺は、5倍体積の1倍PBSを加えた後、ポリトロンホモジナイザーを使用してホモジナイズした。ホモジネートを4℃にて9000rpmで10分間遠心分離した。上清を3000rpmで30分間再び遠心分離して、澄んだ上清を作った。タンパク質濃度は、市販のキット(Pierce、Thermo Scientific)を使用して求めた。
試験物は、次の生物学的材料、すなわち、ヘパリン処置ラット血漿、ヘパリン処置ラット全血、または肺ホモジネートのうちの1つにおいて調製した。血漿および全血サンプルは、995uLのラット血漿または全血に1mg/mLの作業溶液5uLを加えることにより、5000ng/mLで調製した。肺ホモジネートサンプルは、肺ホモジネートをリン酸緩衝溶液(PBS)で1mg/mlのタンパク質濃度に希釈した後、5uLの作業溶液を加えて、995uLの希釈された肺ホモジネートとすることにより調製した。サンプルは、水浴インキュベーターにおいて、穏やかに振盪(65〜75rpm)しながら37℃でインキュベートした。0分、5分、15分、30分、60分、120分、および240分の時点で、インキュベートサンプルの25uLのアリコートを96ウェルプレートに移し、150uLの抽出溶液を使用して、直ちにタンパク質を沈殿させた。インキュベート実験が完了した後、サンプルプレートを4℃にて4000rpmで10分間遠心分離した。その後、ピペット操作装置(Tecan Temo)を使用して、上清を別のプレートに移し、すべてのサンプルに50uLの水を加えた。プレートは、LC−MS分析の前にボルテックスした。
1mg/mLの作業溶液5uLをラット血漿495uLに加えることにより、試験物を50,000ng/mLで調製した。サンプルは、水浴インキュベーターにおいて、穏やかに振盪(65〜75rpm)しながら37℃でインキュベートした。0時間、0.5時間、1時間、2時間、4時間、6時間、および24時間の時点で、インキュベートサンプルの50uLのアリコートを96ウェルプレートに移し、40mMのTCEP(トリス(2−カルボキシエチル)ホスフィン)100uLを各サンプルに加えた。反応混合物を37℃で1時間インキュベートした。反応が完了した後、300uLのアセトニトリルを使用して、タンパク質を沈殿させた。サンプルプレートを4℃にて4000rpmで10分間遠心分離した。その後、ピペット操作装置(Tecan Temo)を使用して、125uLの上清を別のプレートに移し、すべてのサンプルに50uLの水を加えた。プレートは、LC−MS分析の前にボルテックスした。
HPLC:オートサンプラーを備えたAgilent 1290 HPLC
カラム:MAC−MOD ACE C18、3μm、30mm×内径2.1mm
移動相A:0.1%のギ酸アセトニトリル溶液
移動相B:0.1%のギ酸水溶液
データ取得モード:100〜1000m/zの質量範囲での完全走査
データ取得および分析ソフトウェア:MassHunter
安定性アッセイ:安定性半減期(t1/2)の値は、各時点におけるピーク面積を、初期(t=0)ピーク面積を基準とした残存パーセントに変換することにより求めた。
残存パーセント=100×(サンプルピーク面積)÷(t=0ピーク面積)
次の変更を加えて、上述のカルシウムフラックスプロトコールに従った。ペプチドは、ここでも5%ラット血漿(Bioreclamation #RATPLNAHP−M、ヘパリンNa処置したもの)と共にインキュベートした。37℃の組織培養インキュベーターでインキュベートした後、t0およびt24時間の時点で読み取った。分単位のペプチド血漿半減期を、次の計算によって推定した。
1)LN((t0時点のEC50)/(t24時間時点のEC50))
2)上の値の傾きを算出
3)t1/2=0.693/(傾き2)
これらの薬学的に許容される塩を包含する。
− Waters SunFire Prep C18 OBDカラム、5μm、30×100mm、部品番号186002572(カラム1本または連続したカラム2本)
− Waters SunFire Prep C18 OBDカラム、5μm、30×150mm、部品番号186002797
− Waters Atlantis Prep OBD T3カラム、5μm、30×150mm、部品番号186003703
− Waters XBridge Prep C8 OBDカラム、5μm、30×150mm、部品番号186003083
− Machery−Nagel Nucleosil(登録商標)100−5 C18、5μm、250×40mm、部品番号715340.400
1a)HPLC−分析方法A
− カラム:ProntoSil 120−3−C18−H、3μmを備えたBischoff UHC−640(53×4.0mm)、部品番号:0604F185PS030
− 溶離液A:0.07%TFA水溶液/溶離液B:0.1%TFA ACN溶液
− 流量:1.5ml/分
− 温度:40℃
− 勾配:
− カラム:ProntoSil 120−3−C18−H、3μmを備えたBischoff UHC−640(53×4.0mm)、部品番号:0604F185PS030
− 溶離液A:0.1%TFA水溶液/溶離液B:0.4%TFA ACN溶液/溶離液C:MeOH
− 流量:1.5ml/分
− 温度:25℃
− 勾配:
− カラム:XBridge BEH300 C18(100×4.6mm)、3μm、部品番号:186003612
− 溶離液A:0.1%TFA水溶液/溶離液B:0.1%TFA ACN溶液
− 流量:1.0ml/分
− 温度:40℃
− 勾配:
− Waters Acquity UPLC(登録商標)BEH C18、1.7μm、2.1×50mm、部品番号:186002350
− 溶離液A:0.1%FA水溶液、溶離液B:0.1% FA ACN溶液
− 流量:0.7ml/分
− 温度:40℃
− 勾配:
− Waters Acquity UPLC(登録商標)BEH C18、1.7μm、2.1×50mm、部品番号:186002350
− 溶離液A:0.1%FA、溶離液 B:0.1%FA ACN溶液
− 流量:1.0ml/分
− 温度:50℃
− 勾配:4.4分で2〜98%
− カラム:YMC−Gel ODS−A−C18
− 溶離液A:0.1%v/v TFA水溶液/溶離液B:ACN/溶離液A、9/1v/v
− 勾配をかけての溶離:
− Waters Acquity UPLC(登録商標)BEH C18、1.7μm、2.1×50mm、部品番号:186002350
− 溶離液A:0.05%FA+3.75mMの酢酸アンモニウム水溶液、溶離液B:0.04%FA ACN溶液
− 流量:1.0ml/分
− 温度:50℃
− 勾配:1.7分で2〜44%
− Waters Acquity UPLC(登録商標)BEH C18、1.7μm、2.1×50mm、部品番号:186002350
− 溶離液A:0.05%FA+3.75mMの酢酸アンモニウム水溶液、溶離液B:0.04%FA ACN溶液
− 流量:1.0ml/分
− 温度:50℃
− 勾配:4.4分で2〜98%
− Waters Acquity UPLC(登録商標)BEH300 SECガードカラム、4.6×30mm、部品番号:186005793
− 溶離液A:0.1%FA水溶液、溶離液B:0.04%FA ACN溶液
− 流量:1.0ml/分
− 勾配:6分間50%のB
− Waters Acquity UPLC(登録商標)ProSwift RP−3、1.7μm、4.6×50mm、部品番号:064298
− 溶離液A:0.1%FA水溶液、溶離液B:0.08%FA ACN溶液
− 流量:2.0ml/分(2分で3〜80%のB)−流量1.8mL/分
− 温度:40℃
− 勾配:3分で2〜98%
1)最初のアミノ酸の2−クロロトリチルクロリド樹脂への導入およびFmoc除去
2−クロロトリチルクロリド樹脂(1当量、1.0〜1.6mmol/g)をDCMで十分に洗浄した。所望のアミノ酸(通常、1.6mmol/gの導入を考えて、樹脂に対して0.5〜2当量)を、DCM(樹脂1グラムあたり約10mL)およびDIPEA(1.6mmol/gの導入を考えて、樹脂に対して4当量)に溶解させた。溶液を樹脂に加え、懸濁液を室温で19時間振盪した。樹脂を排出し、次いで、DCM/MeOH/DIPEA(17:2:1)、DCM、DMA、DCMで順次、十分に洗浄した。
導入量[mol/g]=(A×Vt×V)/(d×ε×Va×m)
(d:セルの幅、ε=7800L mol−1cm−1)
に従って算出した。
2a)Prelude(商標)合成装置における合成サイクルA
樹脂をDMAで洗浄した。4−メチルピペリジン/DMA(1:4)で繰り返し処理して、Fmocを除去した。樹脂をDMAで洗浄した。Fmoc−アミノ酸(3当量、0.2M NMP溶液)、HCTU(3当量、0.3M NMP溶液)、およびDIPEA(3.3当量、0.66M NMP溶液)を加えた後、懸濁液を、窒素中にて、特定の要件に応じて通常は15分〜4時間、室温で混合することにより、カップリングを行った。DMAで洗浄した後、カップリングステップを、特定の要件に応じて通常は1〜3回繰り返した。DMAで洗浄した後、Ac2O/ピリジン/DMA(1:1:8)の混合物を加え、引き続いて懸濁液を室温で混合することにより、キャッピングを行った。樹脂をDMAで洗浄した。
樹脂をDMAで洗浄した。ピペリジン/DMA(1:4)で繰り返し処理して、Fmocを除去した。樹脂をDMAで洗浄した。Fmoc−アミノ酸(3当量、0.3M NMP溶液)、HCTU(3当量、0.3M NMP溶液)、およびDIPEA(4.5当量、0.9M NMP溶液)を加えた後、懸濁液を、窒素中にて、特定の要件に応じて通常は15分〜4時間、室温で混合することにより、カップリングを行った。DMAで洗浄した後、カップリングステップを、特定の要件に応じて通常は1〜3回繰り返した。DMAで洗浄した後、Ac2O/ピリジン/DMA(1:1:8)の混合物を加え、引き続いて懸濁液を室温で混合することにより、キャッピングを行った。樹脂をDMAで洗浄した。
樹脂をDMFおよびDCMで洗浄した。20%ピペリジン/DMFでの処理(通常、0.1mmolあたり7ml 2回)によって、Fmocを除去した。樹脂をDMFおよびDCMで洗浄した。Fmoc−アミノ酸(5当量、0.2M DMF溶液)、HCTU(5当量、0.5M DMF溶液)、およびDIPEA(10当量、2M NMP溶液)を加えた後、0〜20ワットのマイクロ波電力を用い、懸濁液を、窒素中にて、特定の要件に応じて通常は5〜50分間、75または50℃で混合することにより、カップリングを行った。DMFで洗浄した後、カップリングステップを、特定の要件に応じて1回繰り返してもよいであろう。樹脂をDMFで洗浄した。
3a)切断方法A
樹脂(0.1mmol)を、95%のTFA/EDT/TIS(95:2.5:2.5)水溶液(2mL)と共に室温で通常は1.5〜2時間振盪した。切断溶液を濾別し、新鮮な溶液を加えた(2mL)。懸濁液を室温で通常は0.75〜1時間振盪し、次いで切断溶液を濾別した。新鮮な溶液を加え(2mL)、懸濁液を室温で通常は0.75〜1時間振盪した。切断溶液を濾別した。樹脂を95%TFA水溶液(1mL)で1回すすいだ。合わせた切断および洗浄溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(35mL)上にゆっくりと注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣を冷ヘプタン/ジエチルエーテル(1:1)(10mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。固体を高真空中で乾燥させた。
樹脂(0.1mmol)を95%のTFA/TIS(97.5:2.5)水溶液(2mL)と共に室温で1.5時間振盪した。切断溶液を濾別し、新鮮な溶液を加えた(2mL)。懸濁液を室温で45分間振盪し、切断溶液を濾別した。新鮮な溶液を加え(2mL)、懸濁液を室温で45分間振盪した。切断溶液を濾別した。樹脂を95%TFA水溶液(1mL)で1回すすいだ。合わせた切断および洗浄溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(35mL)上へゆっくりと注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣を冷ヘプタン/ジエチルエーテル(1:1)(10mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。固体を高真空中で乾燥させた。
樹脂(0.1mmol)にHFIP/DCM(10:90)(2mL)を加え、懸濁液を室温で10分間振盪した。切断溶液をiPrOH(0.8mL)中に濾別した。このステップを3回繰り返し、切断溶液は、最初のiPrOH含有切断溶液と直接合わせた。合わせた切断溶液を高真空中で濃縮乾燥した。残渣をtBuOH/H2O(4:1)から凍結乾燥した。
樹脂(0.1mmol)を95%TFA//TIS/DTT(95:2.5:2.5)水溶液(3mL)と共に室温で3時間振盪した。切断溶液を濾別した。樹脂を95%TFA水溶液(1mL)で1回すすいだ。合わせた切断および洗浄溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(10〜15mL)上へゆっくりと注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣にジエチルエーテル(10mL)を加え、懸濁液を3分間ボルテックスし、遠心分離し、上清を廃棄した。洗浄過程を2回繰り返した。固体を高真空中で乾燥させた。
(2−クロロトリチルクロリド樹脂へのFmoc−f−OHの導入、Fmoc除去、および樹脂への導入量の算定)
2−クロロトリチルクロリド樹脂(3.0g、4.80mmol)を、Fmoc−f−OH(1.86g、4.80mmol)をDCM(30mL)およびDIPEA(3.35mL、19.2mmol)に溶かした溶液と、上述の一般手順と同様に反応させて、中間体1a(3.53g、導入量=0.96mmol/g)を得た。
(鎖状ペプチドのアセンブリー)
中間体1a(0.100mmol)を、Prelude(商標)ペプチド合成装置での固相ペプチド合成にかけた。カップリングを以下のとおりに実施した。
(保護基の除去を伴う樹脂からの切断、次いで精製)
中間体1b(0.1mmol)に、95%TFA/EDT/TIS(95:2.5:2.5)水溶液の混合物(2mL)を加え、懸濁液を室温で1.5時間振盪した。切断溶液を濾別し、新鮮な切断溶液(2mL)を加えた。懸濁液を室温で45分間振盪し、次いで切断溶液を濾別した。新鮮な溶液(2mL)を加え、懸濁液を室温で45分間振盪した。切断溶液を濾別し、樹脂を95%TFA水溶液(1mL)で洗浄した。合わせた切断および洗浄溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(35mL)上へ注ぎ、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣を冷ヘプタン/ジエチルエーテル(1:1)(10mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。固体を高真空中で乾燥させた。粗生成物を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、実施例1(86.5mg、0.044mmol)を得た。
(2−クロロトリチルクロリド樹脂へのFmoc−f−OHの導入、Fmoc除去、および樹脂の導入量の算定)
2−クロロトリチルクロリド樹脂(2g、3.20mmol)を、Fmoc−f−OH(992mg、2.56mmol)をDCM(20mL)およびDIPEA(2.236mL、12.80mmol)に溶かした溶液と、上述の一般手順と同様に反応させて、中間体29a(2.36g、導入量=0.82mmol/g)を得た。
(鎖状ペプチドのアセンブリー)
中間体29a(0.600mmol)を、Prelude(商標)ペプチド合成装置での固相ペプチド合成にかけた。カップリングを以下のとおりに実施した。
(保護基の除去を伴う樹脂からの切断、次いで精製)
中間体29b(0.6mmol)に95%TFA/EDT/TIS(95:2.5:2.5)水溶液の混合物(10mL)を加え、懸濁液を室温で2時間振盪した。切断溶液を濾別し、新鮮な切断溶液(10mL)を加えた。懸濁液を室温で1時間振盪し、次いで切断溶液を濾別した。新鮮な溶液(10mL)を加え、懸濁液を室温で1時間振盪した。切断溶液を濾別した。合わせた切断溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(200mL)上へ注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣を冷ヘプタン/ジエチルエーテル(1:1)(100mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。固体を高真空中で乾燥させた。粗生成物を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、実施例29(538.7mg、0.279mmol)を得た。
(線状ペプチドのアセンブリー)
フェネチルアミン−BAL−PS樹脂(167mg、0.100mmol)を、Prelude(商標)ペプチド合成装置での固相ペプチド合成にかけた。カップリングを以下のとおりに実施した。
(保護基の除去を伴う樹脂からの切断、次いで精製)
中間体32a(0.1mmol)に、95%のTFA/EDT/TIS(95:2.5:2.5)水溶液の混合物(2mL)を加え、懸濁液を室温で1.5時間振盪した。切断溶液を濾別し、新鮮な切断溶液(2mL)を加えた。懸濁液を室温で1.5時間振盪し、次いで切断溶液を濾別した、新鮮な溶液(2mL)を加え、懸濁液を室温で2時間振盪した。切断溶液を濾別し、樹脂を95%TFA水溶液(1mL)で洗浄した。合わせた切断溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(35mL)中に注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した、残渣を冷ヘプタン/ジエチルエーテル(1:1)(5mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。固体を高真空中で乾燥させた。粗生成物を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、実施例32(37.0mg、0.020mmol)を得た。
(鎖状ペプチドのアセンブリー)
Fmoc保護されたRink−アミド−AM−PS−樹脂(217mg、0.100mmol)を、Prelude(商標)ペプチド合成装置での固相ペプチド合成にかけた。カップリングを以下のとおりに実施した。
(保護基の除去を伴う樹脂からの切断、次いで精製)
中間体33a(0.1mmol)に95%TFA/TIS(97.5:2.5)水溶液の混合物(2mL)を加え、懸濁液を室温で1.5時間振盪した。切断溶液を濾別し、新鮮な切断溶液(2mL)を加えた。懸濁液を室温で45分間振盪し、次いで切断溶液を濾別した。新鮮な溶液(2mL)を加え、懸濁液を室温で45分間振盪した。切断溶液を濾別し、樹脂を95%TFA水溶液(1mL)で洗浄した。合わせた切断溶液を、冷ヘプタン/ジエチルエーテル(1:1)の混合物(35mL)上へ注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣を冷ヘプタン/ジエチルエーテル(1:1)(10mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。固体を高真空中で乾燥させた。粗生成物を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、実施例33(108.9mg、0.055mmol)を得た。
(2−クロロトリチルクロリド樹脂へのFmoc−nle−OHの導入、Fmoc除去、および樹脂への導入量の算定)
2−クロロトリチルクロリド樹脂(300mg、0.48mmol)を、Fmoc−Nle−OH(136mg、0.384mmol)をDCM(3mL)およびDIPEA(0.335mL、1.92mmol)に溶かした溶液と、上述の一般手順と似たようにして反応させて、中間体43a(329mg、導入量=0.99mmol/g)を得た。
(線状ペプチドのアセンブリー)
中間体43a(0.100mmol)を、Prelude(商標)ペプチド合成装置での固相ペプチド合成にかけた。カップリングを以下のとおりに実施した。
(樹脂からのHFIP切断)
中間体43b(0.100mmol)にHFIP/DCM(10:90)(2mL)を加え、懸濁液を室温で10分間撹拌した。切断溶液をiPrOH(0.8mL)中に濾別した。このステップを3回繰り返し、切断溶液を最初のiPrOH含有切断溶液と直接合わせた。合わせた切断溶液を高真空中で濃縮乾燥した。残渣をtBuOH/H2O(4:1)から凍結乾燥して、中間体43cを得た。
(4−フェノキシピペリジンのカップリング)
HATUを有する中間体43c(49.4mg、0.130mmol)、HOAt(17.7mg、0.130mmol)、および2,6−ルチジン(0.233mL、2.000mmol)をNMP(5mL)に混ぜた混合物を、室温で5分間撹拌した。4−フェノキシピペリジン(35.0mg、0.197mmol)を加え、室温で45分間撹拌を続けた。反応混合物を真空中で濃縮乾燥して、中間体43dを得た。
(保護基の除去および精製)
中間体43dを95%TFA/EDT/TIS(95:2.5:2.5)水溶液(5mL)に溶解させ、溶液を室温で2時間撹拌した。切断溶液を冷ヘプタン/ジエチルエーテル(1:1)(35mL)へ注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣を冷ヘプタン/ジエチルエーテル(1:1)(5mL)で洗浄し、懸濁液を遠心分離し、上清を廃棄した。残渣を高真空中で乾燥させた。生成物を分取HPLCによって単離し、ACN/H2Oから凍結乾燥して、実施例43(19.3mg、0.010mmol)を得た。
(2−クロロトリチルクロリド樹脂へのFmoc−f−OHの導入、Fmoc除去、および樹脂への導入量の算定)
2−クロロトリチルクロリド樹脂(5.0g、8.01mmol)を、Fmoc−f−OH(3.10g、8.01mmol)をDCM(50mL)およびDIPEA(5.59mL、32.0mmol)に溶かした溶液と、上述の一般手順と同様に反応させて、中間体57a(5.87g、導入量=0.897mmol/g)を得た。
(鎖状ペプチドのアセンブリー)
中間体57a(0.100mmol)をLiberty(商標)マイクロ波ペプチド合成装置での固相ペプチド合成にかけた。カップリングを次のとおりに実施した。
(保護基の除去を伴う樹脂からの切断、次いで精製)
中間体57b(0.1mmol)に95%TFA/EDT/DTT(95:2.5:2.5)水溶液の混合物(3mL)を加え、懸濁液を室温で3時間振盪した。切断溶液を濾別し、樹脂を95%TFA(1mL)水溶液で洗浄した。合わせた切断および洗浄溶液を冷ヘプタン/ジエチルエーテル(1:1)の混合物(11mL)上へ注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣にジエチルエーテル(10mL)を加え、懸濁液を3分間ボルテックスし、遠心分離し、上清を廃棄した。洗浄過程を2回繰り返した。固体を高真空中で乾燥させた。粗生成物を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、実施例57(59mg、0.030mmol)を得た。
− 実施例2〜28は、実施例1と同様に合成した。
− 実施例30および31は、実施例29と同様に合成した。
− 実施例34〜42は、実施例33と同様に合成した。
− 実施例44〜56および58〜63は、実施例57と同様に合成した。
ステップ1:中間体64c(PPA−O2Oc−O2Oc−O2Oc−O2Oc−Q−R−P−R−L−a−H−K−G−P−f−a−f−OH)の合成
(鎖状ペプチドのアセンブリー)
H−f−O−PS(1.0mmol)をLiberty(商標)マイクロ波ペプチド合成装置での固相ペプチド合成にかけた。カップリングを次のとおりに実施した。
(保護基の除去を伴う樹脂からの切断、次いで精製)
25mLのTFA/TIPS/水(95:2.5:2.5)中の3.09gのDTTおよび3mLのチオアニソールでできた溶液に、中間体64a(1.0mmol)を加え、懸濁液を室温で3時間振盪した。切断溶液を濾別し、樹脂を95%TFA水溶液(5mL)で洗浄した。合わせた切断および洗浄溶液を冷ジエチルエーテル(80mL)へ注いで、沈殿を得た。懸濁液を遠心分離し、上清を廃棄した。残渣にジエチルエーテル(80mL)を加えた。懸濁液を3分間ボルテックスし、遠心分離し、上清を廃棄した。洗浄過程を3回繰り返した。固体を高真空中で乾燥させた。粗生成物を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、中間体64bを白色の粉末(235mg、84μmol)として得た。
中間体64b(76mg、29μmol)、2,2’−ジチオジピリジン(19mg、86μmol)のACN(1mL)中混合物を25℃で1時間振盪した。反応混合物をMeOHで希釈し、濾過した。溶液を分取HPLCによって精製し、ACN/H2Oから凍結乾燥して、中間体64cを白色の粉末(28mg、10μmol)として得た。
− TCEPによる脱キャッピング
15mLチューブに入った、アルブミン(500mg、Aldrich、ヒト血清からの凍結乾燥粉末)を10mLのPBS 1×緩衝液に溶かした溶液に、TCEP塩酸塩の溶液(生物学グレード精製水中1.074mg)を一度に加えた。得られた溶液を室温で1時間振盪し、次いで脱塩し、2本のAmicon Ultra−4遠心式フィルター(30K MWCO)で洗浄した。フィルターを4K gで40分間スピンにかけ、濾液を廃棄した。各フィルターに3mLの生物学グレード精製水を加えてそれぞれ洗浄し(14K gで10分間スピンにかけ)、洗浄過程を3回繰り返した。脱キャッピングされたHSAを水(合計約20mL)に溶解させた。溶液を50mLのFalconチューブに移し、凍結乾燥して、結晶質の粉末(500mg)を得た。
2mLチューブに入った、この脱キャッピングされたHSA(2mg)を400μLのPBS pH7.4に溶かした溶液に、6−マレイミドヘキサン酸(13μg)の水溶液を加えた。得られた溶液を室温で2時間振盪した。UPLC−MS(分析方法J)によって、単一付加物の生成だけが示された。測定値:66649.0、予想値:66648。
15mLチューブに入った、アルブミン(400mg、Aldrich、ヒト血清からの凍結乾燥粉末)を5mLのPBS 1×緩衝液に溶かした溶液に、DTTの溶液(0.232μl、生物学グレード精製水中2mg/mL)を一度に加えた。得られた溶液を室温で2時間振盪し、次いで脱塩し、20本のAmicon Ultra−0.5遠心式フィルター(10K MWCO)で洗浄した。フィルターを14K gで10分間スピンにかけ、濾液を廃棄した。各フィルターの頂部に生物学グレード精製水を加えてそれぞれ洗浄し(14K gで10分間スピンにかけ)、洗浄過程を6回繰り返した。脱キャッピングされたHSAを水(合計約20mL)に溶解させた。溶液を50mLのFalconチューブに移し、凍結乾燥して、結晶質の粉末(376mg)を得た。
2mLチューブに入った、この脱キャッピングされたHSA(3mg)を400μLのPBS pH7.4に溶かした溶液に、3−マレイミドプロピオン酸(25μg)の水溶液を加えた。得られた溶液を室温で終夜振盪した。UPLC−MS(分析方法J)によって、単一付加物の生成だけが示された。測定値:66608.0、予想値:66606。
2mLチューブに入った、アルブミン(120mg、Aldrich、ヒト血清からの凍結乾燥粉末)を1mLの50mM PBS緩衝液pH8.0に溶かした溶液に、システイン(10.94mg)を一度に加えた。得られた溶液を室温で1時間振盪し、次いで脱塩し、2本のAmicon Ultra−0.5遠心式フィルター(10K MWCO)で洗浄した。フィルターを14K gで10分間スピンにかけ、濾液を廃棄した。各フィルターの頂部に生物学グレード精製水を加えてそれぞれ洗浄し(14K gで10分間スピンにかけ)、洗浄過程を5回繰り返した。脱キャッピングされたHSAを、水(合計4mL)に溶解させた。溶液を15mLのFalconチューブに移し、凍結乾燥して、結晶質の粉末(108mg)を得た。
2mLチューブに入った、この脱キャッピングされたHSA(3mg)を500μLのPBS pH7.4に溶かした溶液に、3−マレイミドプロピオン酸(15μg)の水溶液を加えた。得られた溶液を室温で1時間振盪した。UPLC−MS(分析方法J)によって、単一付加物の生成だけが示された。測定値:66608.0、予想値:66606。
脱キャッピングされたHSA(100mg)のPBS緩衝液(6mL)溶液を、中間体64cの溶液(水中7.8mg)で処理した。得られた溶液を室温で1時間振盪し、次いで脱塩し、4本のAmicon Ultra−0.5遠心式フィルター(10K MWCO)で洗浄した。フィルターを13K gで10分間スピンにかけ、濾液を廃棄した。各フィルターの頂部に生物学グレード精製水を加えてそれぞれ洗浄し(13K gで10分間スピンにかけ)、洗浄過程を6回繰り返した。コンジュゲートを水(合計4mL)に溶解させた。溶液を15mLのFalconチューブに移し、凍結乾燥して、結晶質の粉末(90.5mg)を得た。
Claims (32)
- 次式:
X1は、ポリペプチドのN末端であり、存在しないかまたはpEのいずれかであり、
X2は、Rまたはrであり、
X3は、Pまたは4−PhPであり、
X5は、L、Cha、D−L、F、Y、Y(Bzl)、3,4−Cl2−F、またはNaIであり、
X6は、D−アミノ酸、S、またはAであり、
X7は、D−アミノ酸、L、H、またはAibであり、X6およびX7の少なくとも一方は、D−アミノ酸またはAibであり、
X8は、K、k、Q、またはEであり、
X9は、GまたはDであり、
X10は、Pまたはピペコリン酸であり、
X11は、D−Nle、Nle、f、またはD−Nvaであり、
X12は、存在しない、P、またはD−アミノ酸であり、
X13は、C末端であり、存在しない、F、またはD−アミノ酸であり、X11、X12、およびX13の少なくとも1つは、D−アミノ酸であり、
Nleは、L−ノルロイシンであり、
D−Nleは、D−ノルロイシンであり、
Nalは、L−ナフチル)アラニンであり、
D−Nvaは、D−ノルバリンであり、
Aibは、α−アミノイソ酪酸であり、
Chaは、(S)−β−シクロヘキシルアラニンであり、
D−Ticは、D−1,2,3,4−テトラヒドロイソキノリン−3−カルボン酸であり、
pEは、L−ピログルタミン酸であり、
3,4−Cl2−Fは、(S)−3,4−ジクロロフェニルアラニンであり、
Yは、L−チロシンであり、
Y(Bzl)は、L−ベンジル−チロシンである]
を有するポリペプチド、またはポリペプチドのアミド、エステル、もしくは塩、またはこれらと実質的に同等なポリペプチド。 - X6およびX12がD−アミノ酸である、請求項1に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X13がD−アミノ酸である、請求項2に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X11がD−アミノ酸である、請求項3に記載のポリペプチド、またはそのアミド、塩のエステル。
- X6およびX13がD−アミノ酸である、請求項1に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X7およびX12がD−アミノ酸である、請求項1に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X13がD−アミノ酸である、請求項6に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- 次式:
- 式III:
- 式IV:
- X6が、a、D−Leu、k、s、d、nva、abu、f、h、v、およびD−Cys(tBu)から選択されるD−アミノ酸である、請求項1から9のいずれか一項に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X7が、Aibである、またはa、f、およびhから選択されるD−アミノ酸である、請求項1から11のいずれか一項に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X12が、存在しない、またはa、f、p、e、r、abu、nva、およびD−Leuから選択されるD−アミノ酸である、請求項1から12のいずれか一項に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X13が、存在しない、またはf、y、d、およびD−Ticから選択されるD−アミノ酸である、請求項1から13のいずれか一項に記載のポリペプチド、またはそのアミド、エステル、もしくは塩。
- X13が、存在しないまたはfである、請求項14に記載のポリペプチド、またはポリペプチドのアミド、エステル、もしくは塩。
- X1がpEである、前記請求項のいずれか一項に記載のポリペプチドまたはポリペプチドのアミド、エステル、もしくは塩。
- X5がLである、請求項1から16のいずれか一項に記載のポリペプチドまたはポリペプチドのアミド、エステル、もしくは塩。
- X8がKである、請求項1から17のいずれか一項に記載のポリペプチドまたはポリペプチドのアミド、エステル、もしくは塩。
- X11がNleまたはnleである、請求項1から18のいずれか一項に記載のポリペプチドまたはポリペプチドのアミド、エステル、もしくは塩。
- C末端がアミドである、前記請求項のいずれか一項に記載のポリペプチドまたはポリペプチドの塩。
- C末端が、式−C(O)−R2のアミドであり、R2が、−NH2、−NH−(CH2)2−Ph、または4−フェノキシピペリジンである、請求項20に記載のポリペプチド、またはポリペプチドの塩。
-
-
- 血漿安定性が少なくとも100分であり、IC50が10nM未満である、前記請求項のいずれか一項に記載のポリペプチド。
- その必要のある対象において、APJ受容体のアゴニズムに反応を示す疾患または障害を治療または予防する方法であって、治療有効量の請求項1から24のいずれか一項に記載のポリペプチドまたはそのアミド、エステル、もしくは塩を対象に投与することを含む方法。
- 疾患または障害が、急性代償不全心不全(ADHF)、慢性心不全、肺高血圧、心房細動、Brugada症候群、心室性頻拍、アテローム性動脈硬化症、高血圧、再狭窄、虚血性心血管疾患、心筋症、心臓線維症、不整脈、水分貯留、糖尿病(妊娠糖尿病を含める)、肥満、末梢動脈疾患、脳血管発作、一過性脳虚血発作、外傷性脳損傷、筋萎縮性側索硬化症、熱傷(日焼けを含める)、および子癇前症から選択される、請求項25に記載の方法。
- 医薬として使用するための、請求項1から24のいずれか一項に記載のポリペプチドまたはそのアミド、エステル、もしくは塩。
- APJ受容体のアゴニズムに反応を示す疾患または障害の治療または予防において使用するための、請求項1から24のいずれか一項に記載のポリペプチドまたはそのアミド、塩のエステル。
- 急性代償不全心不全(ADHF)、慢性心不全、肺高血圧、心房細動、Brugada症候群、心室性頻拍、アテローム性動脈硬化症、高血圧、再狭窄、虚血性心血管疾患、心筋症、心臓線維症、不整脈、水分貯留、糖尿病(妊娠糖尿病を含める)、肥満、末梢動脈疾患、脳血管発作、一過性脳虚血発作、外傷性脳損傷、筋萎縮性側索硬化症、熱傷(日焼けを含める)、または子癇前症の治療において使用するための、請求項1から24のいずれか一項に記載のポリペプチドまたはそのアミド、塩のエステル。
- 治療有効量の請求項1から24のいずれか一項に記載のポリペプチドまたはそのアミド、エステル、もしくは塩と、治療上活性な1種または複数の共薬剤(co-agent)とを含む組合せ。
- 共薬剤が、イノトロープ、βアドレナリン受容体遮断薬、HMG−CoA還元酵素阻害薬、アンジオテンシンII受容体アンタゴニスト、アンジオテンシン変換酵素(ACE)阻害薬、カルシウムチャネル遮断薬(CCB)、エンドセリンアンタゴニスト、レニン阻害薬、利尿薬、ApoA−I模倣薬、抗糖尿病薬、肥満減少薬、アルドステロン受容体遮断薬、エンドセリン受容体遮断薬、アルドステロンシンターゼ阻害薬(ASI)、CETP阻害薬、抗凝血薬、リラキシン、BNP(ネシリチド)、および/またはNEP阻害薬から選択される、請求項30に記載の組合せ。
- 治療有効量の請求項1から24のいずれか一項に記載のポリペプチドまたはそのアミド、エステル、もしくは塩と、1種または複数の薬学的に許容される担体とを含む医薬組成物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2021530562A (ja) * | 2018-07-05 | 2021-11-11 | ビオゼウス・デゼンヴォルヴィメント・ジ・プロドゥトス・ビオファルマセウティコスBiozeus Desenvolvimento De Produtos Biofarmaceuticos | 合成ペプチド、プロドラッグ、医薬組成物および使用 |
JP7317956B2 (ja) | 2018-07-05 | 2023-07-31 | ビオゼウス・デゼンヴォルヴィメント・ジ・プロドゥトス・ビオファルマセウティコス | 合成ペプチド、プロドラッグ、医薬組成物および使用 |
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EP2922559A2 (en) | 2015-09-30 |
EP2922559B1 (en) | 2018-10-10 |
AR093559A1 (es) | 2015-06-10 |
ES2705323T3 (es) | 2019-03-22 |
US20150284446A1 (en) | 2015-10-08 |
US10005829B2 (en) | 2018-06-26 |
JP6444882B2 (ja) | 2018-12-26 |
CN105007928B (zh) | 2018-03-20 |
WO2014081702A3 (en) | 2014-07-17 |
CN105007928A (zh) | 2015-10-28 |
UY35144A (es) | 2014-06-30 |
TW201425339A (zh) | 2014-07-01 |
WO2014081702A2 (en) | 2014-05-30 |
WO2014081702A4 (en) | 2014-09-04 |
JP2018172410A (ja) | 2018-11-08 |
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