JP6143740B2 - 持続性ペプチド類似体 - Google Patents
持続性ペプチド類似体 Download PDFInfo
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- JP6143740B2 JP6143740B2 JP2014503985A JP2014503985A JP6143740B2 JP 6143740 B2 JP6143740 B2 JP 6143740B2 JP 2014503985 A JP2014503985 A JP 2014503985A JP 2014503985 A JP2014503985 A JP 2014503985A JP 6143740 B2 JP6143740 B2 JP 6143740B2
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- Prior art keywords
- acid
- peptide
- adrenomedullin
- intermedin
- seq
- Prior art date
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Description
ヘイ(Hay)及びスミス(Smith)著,「Trends in Pharmacological Sciences(Trends Pharmacol.Sci.)」,2001年,第22刊,p.57−59、及びシンドウ(Shindo)等著,「Circulation」,2001年,第104刊,1964−197は、脈管構造におけるアドレノメデュリンの重要性を検討している。CGRPの役割は、ツァン(Zhang)等著,2001年,「Pain」,第89刊,p.265−273、サーモン(Salmon)等著,「Neuroreport」,1999年,第10巻,p.849−854、及びサーモン(Salmon)等著,「Nature Neuroscience(Nat.Neurosci.)」,2001年,第4刊,p.357−358に検討されている。アミリンの役割は、マルダー(Mulder)等著,「American Journal of Physiology − Endocrinology and Metabolism(Am.J.Physiol.Endocrinol.Metab.)」,2000年,第278刊,E684−691に検討されている。
インテルメジン及びアドレノメデュリンの薬理学的活性の観点から、多くの臨床上の適応が明らかであり、高血圧症、例えば妊婦高血圧症、肺動脈高血圧症、糖尿病に伴う高血圧症など、気管支肺異形成症、創傷治癒などが挙げられるが、これらに限定されない。例えば、インテルメジンペプチド、アドレノメデュリンペプチド又はこれらの変異体が使用される臨床上の適応は、特には高血圧症の処置である。本発明の類似体は、血圧を降下させ、例えば、心拍数に悪影響を及ぼすことなく収縮期圧を少なくとも約5%、少なくとも約10%、少なくとも約15%、少なくとも約20%又はそれ以上降下させる。
本発明の組成物は、治療投与のための種々の処方に組み込まれ得る。特に、インテルメジン若しくはアドレノメデュリンの活性を調整する薬剤、又はインテルメジンポリペプチド若しくはアドレノメデュリンポリペプチド及びそれらの類似体は、これらの活性が不必要に高いか又は低いインテルメジン又はアドレノメデュリンの機能障害を処置すべく患者に投与するために処方され得る。更に具体的には、本発明の化合物は、適切な薬学的に許容可能な担体又は希釈剤と組み合わせることによって医薬組成物に処方されることができ、錠剤、カプセル剤、粉末剤、顆粒剤、軟膏剤、液剤、坐剤、注入剤、吸入剤、ゲル剤、微粒子剤及び噴霧剤のような固形、半固形、液体又はガスの形態の製剤に処方されてもよい。このように、本化合物の投与は、種々の方法で行われることができ、例えば、経口投与、舌下投与、直腸投与、非経口投与、腹腔内投与、皮内投与、経皮投与、気管内投与などが挙げられる。活性剤は、投与後全身に作用してもよく、又は移植部位で活性量を保持するように作用する移植片を使用して局在化されてもよい。
以下の実施例は、本発明を構成して使用する方法の完全な開示及び記載を当業者に提供するために提示されており、本発明者が本発明とみなすものの範囲を限定するものではなく、以下の実験例は行われた全ての実験例又は行われた唯一の実験例であることを示すものでもない。使用される数値(例えば、量、温度など)に関して正確さを確保するように努力しているが、多少の実験誤差及び偏差も存在する。特に示されていない限り、部は重量部であり、分子量は重量平均分子量であり、温度は摂氏温度であり、圧力は、大気圧又は大気圧に近い圧力である。
インテルメジンの修飾
標準的な固相Fmocペプチド化学(フィールズ ジービー(Fields GB)及びノーブル アールエル(Noble RL)著,「Solid phase peptide synthesis utilizing 9−fluorenylmethoxycarbonyl amino acids」,「International Journal of Peptide and Protein Research(Int J Pept Protein Res)」,1990年,第35刊,p.161−214)を用いて、スタンフォード大学(Stanford University)のPan Facilityによって、アプライドバイオシステムズ(Applied Biosystems)社製の自動ペプチド合成装置を用いてペプチドを合成した。ペプチドの合成中に、共役されているリジン残基をFmoc−保護[C16]パルミチン酸塩脂肪酸(Lys(PAL))に取り込むことによって修飾ペプチドを合成した。純度を、逆相HPLCによって測定し、その後エレクトロスプレーイオン化質量分析を使用して特徴付けた。
アドレノメデュリンの修飾
標準的な固相Fmocペプチド化学(フィールズ ジービー(Fields GB)及びノーブル アールエル(Noble RL)著,「Solid phase peptide synthesis utilizing 9−fluorenylmethoxycarbonyl amino acids」,「International Journal of Peptide and Protein Research(Int J Pept Protein Res)」,1990年,第35刊,p.161−214)を用いて、スタンフォード大学(Stanford University)のPan Facilityによって、アプライドバイオシステムズ(Applied Biosystems)社製の自動ペプチド合成装置を用いてペプチドを合成した。ペプチドの合成中に、共役されているリジン残基をFmoc−保護[C16]パルミチン酸塩脂肪酸(Lys(PAL))に取り込むことによって修飾ペプチドを合成した。純度を、逆相HPLCによって測定し、その後エレクトロスプレーイオン化質量分析を使用して特徴付けた。
ADM及びADM−PAの刺激効果の一般的な実例を図7に示す。
アドレノメデュリンペプチドを、10〜20%のDMSOを含む生理食塩水に10マイクロモル/リットルで溶解した。注入の前に、ペプチドのアリコートをPBSに溶解し、注入液の最終容積を200μlとした。血圧測定を、測定手順に前適応させた覚醒SHRラット(9〜16週齢)で行った。間接的収縮期圧を、テイル−カフ(tail−cuff)法(ケント サイエンティフィック社(Kent Scientific Corporation))を用いてプログラム可能な非侵襲性血圧システムによって測定した。圧力変換器を取り付けた後、ラットを10分間そのままにしておき、その後10〜15分の間隔を置いてベースラインの測定を行った。ベースラインの測定後、様々な用量のペプチド、又は10%DMSOを含む生理食塩水をラットの腹腔内に注入した。血圧及び心拍数を、20秒間隔で20〜40分モニターした。血圧の変化を、所与の時間間隔内で行われた測定結果の平均として計算した。
Claims (8)
- R1 は、パルミチン酸塩、ステアリン酸塩、アラキジン酸、ラウリン酸、ミリスチン酸、ミリストレイン酸、パルミトオレイン酸、サピエン酸、オレイン酸、リノール酸、α−リノレン酸、アラキドン酸、エイコサペンタエン酸、エルカ酸及びドコサヘキサエン酸から選択されていることを特徴とする請求項1に記載のペプチド。
- 前記ペプチドは、配列番号7に記載のアミノ酸配列を含み、R1 は、パルミチン酸塩であることを特徴とする請求項1に記載のペプチド。
- 前記ペプチドは、配列番号6に記載のアミノ酸配列を含み、R1 は、パルミチン酸塩であることを特徴とする請求項1に記載のペプチド。
- 治療有効量の請求項1〜4のいずれか1つに記載のペプチドと、薬学的に許容可能な誘導体とを含んでいることを特徴とする医薬組成物。
- CLR/RAMP受容体の活性のために宿主動物に長時間導入する持続性作用薬を製造する方法であって、
前記持続性作用薬に、請求項5に記載の医薬組成物が含まれていることを特徴とする方法。 - 個体の心拍出量を増加させながら、末梢血圧を下げるための薬剤であって、4時間毎に1回を超える時間間隔で導入される前記薬剤を製造する方法であって、
前記薬剤に、請求項5に記載の医薬組成物が含まれていることを特徴とする方法。 - 前記薬剤は、12時間毎に1回を超える時間間隔で導入されるものであることを特徴とする請求項7に記載の方法。
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US10464983B2 (en) | 2015-05-13 | 2019-11-05 | The Board Of Regents Of The University Of Oklahoma | Variants of adrenomedullin and calcitonin gene-related peptide and methods of use |
BR112018004208A2 (ja) * | 2015-09-18 | 2018-09-25 | University Of Miyazaki | Prolonged operation type Adreno medullin derivative |
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US11701409B2 (en) | 2016-02-09 | 2023-07-18 | Adepthera Llc | Dosing and use of long-acting CLR/ramp agonists |
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