JP2006342170A - ウロテンシン−iiアゴニスト及びアンタゴニスト - Google Patents
ウロテンシン−iiアゴニスト及びアンタゴニスト Download PDFInfo
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- JP2006342170A JP2006342170A JP2006185286A JP2006185286A JP2006342170A JP 2006342170 A JP2006342170 A JP 2006342170A JP 2006185286 A JP2006185286 A JP 2006185286A JP 2006185286 A JP2006185286 A JP 2006185286A JP 2006342170 A JP2006342170 A JP 2006342170A
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
Abstract
【解決手段】ウロテンシンーIIのポリペプチドのC末端保存領域におけるアミノ酸配列を基本に各種ポリペプチドの合成およびその生理活性を解析し、有効と判定される環状ポリペプチドを選択する。更に、ウロテンシン−IIの過剰または過小発現に特徴付けられる生理学的または心理学的状態を治療する為の方法をも特徴とする。
【選択図】 なし
Description
別の好ましいポリペプチドにおいては、AA1はCpaであり、AA2はD−Cysであり、AA3はPheであり、AA4はTrpであり、AA5はLysであり、AA6はThrであり、そして、AA7はValである。
定義
‘ポリペプチド’によって、ペプチド結合または修飾ペプチド結合によって互いにつながれた2またはそれを超えるアミノ酸を含んでなる、あらゆるペプチド(環状ペプチドを包含する)またはタンパク質が意味される。“ポリペプチド”とは、一般的にペプチド、オリゴペプチド、またはオリゴマーと呼ばれる短い鎖、及び一般的にタンパク質と呼ばれるより長い鎖の両方をのことを言う。ポリペプチドは、遺伝子にコードされた20アミノ酸より他のアミノ酸を含有しうる。“ポリペプチド”は、天然の方法によってか、または当該分野において周知の化学的修飾技術によって修飾されるアミノ酸配列を包含する。修飾は、ペプチド主鎖、アミノ酸側鎖、及びアミノまたはカルボキシ末端を包含する、ポリペプチドのあらゆる場所で起こり起こりうる。
“アリール”によって、その環部分に6〜12の炭素を、好ましくはフェニル、ナフチル、またはテトラヒドロナフチルのように、その環部分に6〜10炭素を含有する単環式または二環式芳香族基が意味される。“アリールアルキル”によって、ベンジル、フェニルエチル、または2−ナフチルメチルのような、アリール置換基を有する本明細書で説明されたアルキル基が意味される。
好ましい態様においては、各々の置換基Yは、NO2、CN、Cl、Br、I、F、Me、COR4、COOR4、またはOR4基を独立して表し、R4は、HまたはC1〜C8アルキルである。芳香族アミノ酸の例には、Phe、Cpa、Trp、Pal、His、β−Nal、3−ピリジル−Ala、4−ピリジル−Ala、2,4−ジクロロ−Phe、ペンタフルオロ−Phe、p−Z−Phe、及びo−Z−Phe(式中、Zは、Me、Cl、Br、F、OH、OMe、及びNO2からなる群から選択される。)が含まれるが、これらに限定されない。
段階1:Boc−4−クロロフェニルアラニン−S−メチルベンジル−D−システイン−3−ピリジル−2−アニラン−D−トリプトファン−Nε−ベンジルオキシカルボニルリジン−バリン−S−メチルベンジルシステイン−4−クロロフェニルアラニン−ベンズヒドリルアミンレジンの調製。
段階2:脱保護及びレジンからの切り離し
段階1に記載されたレジン(1.0g,0.25mmol)が、アニソール(5mL)、ジチオスレイトール(100mg)、及び無水フッ化水素酸(35mL)と約0℃で混合され、そして45分間攪拌された。過剰のフッ化水素酸が乾燥窒素気流下で迅速に留去され、その後、遊離ペプチドが沈殿させられ、そしてエーテルで洗浄された。次いで、粗精製のペプチドが、500mLの90%酢酸中に溶解された。I2/メタノールの濃縮溶液が持続性の茶色が観測されるまで加えられた。過剰のI2が、アスコルビン酸の添加によって除去され、そしてその溶液は小容量に濃縮され、それが、VYDACTMオクタデシルシランシリカ(10〜15μm)のカラム(2.5×90cm)に付された。これが、アセトニトリルの0.1%トリフルオロ酢酸水中でのリニアグラジェントで溶出された。画分は、薄層クロマトグラフィー及び分析的高速液体クロマトグラフィーによって検査され、そして最大純度を与えるまでプールされた。水からなる溶液の繰り返し凍結乾燥が、125mgの望まれる生成物を、白色のふわふわした粉末として与えた。
実施例2:U−IIアンタゴニストをアッセイする為のラット大動脈環状細片の使用
実験の前に5〜7日間隔離された雄Sprague−Dawleyラット(250〜350g)が、断頭で犠牲にされた(実験は、Tulane医科大学の動物供給源についての諮問委員会によって承認された)。胸部大動脈は、切り裂かれ、結合性組織から遊離され、そして幅およそ1.5mmで輪切りにされた。その輪は、高カリウムKreb’s溶液(9.15g/L塩化カリウム、2.1g/L炭酸水素ナトリウム、1.0g/Lグルコース、0.16g/Lリン酸2水素カリウム、0.14g/L硫酸マグネシウム(無水)、及び0.22g/L塩化カルシウム(2水和物))を含有する15mLオーガンバス中へ吊るされた。
本発明は好ましい態様を参照して説明されてきたが、当業者は、その本質的特徴を容易に理解することができ、そして、本発明の精神及び範囲を逸脱することなく、本発明を様々な使用及び条件に適合させる為の様々な変更及び修飾をすることができる。当業者は、日常の実験だけを使用して、本明細書に記載された発明の具体的態様の多くの均等なものを認識または確認することができるであろう。そのような均等物は、本発明の範囲に含まれることが意図される。
Claims (27)
- ポリペプチドまたはその変異体であって、前記ポリペプチドが、式:
(R1)a−AA1−シクロ[AA2−AA3−AA4−AA5−AA6−Cys]−AA7−R2
(式中、
AA1は、芳香族アミノ酸のL異性体であり;
AA2は、CysのLまたはD異性体であり;
AA3は、芳香族アミノ酸のL異性体であり;
AA4は、TrpのLまたはD異性体であり;
AA5は、Lys、N−Me−Lys、またはOrnのLまたはD異性体であり;
AA6は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nle、または芳香族アミノ酸のLまたはD異性体であり;
AA7は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nle、または芳香族アミノ酸のLまたはD異性体であり;
R1は、H、低級アルキル、低級アルカノイル、または低級アシルであって;aは、1または2であり;そして、R2は、OH、OR3、N(R3)2、またはNHR3であって、ここでR3は、H、低級アルキル、またはアリールアルキルである。)
を有するポリペプチド、または前記ポリペプチドもしくは変異体の薬学的に許容できる塩。但し、前記ペプチドはCpa−c[D−Cys−Pal−D−Trp−Lys−Val−Cys]−Cpa−NH2ではない。 - 請求項1記載のポリペプチドであって、AA3が、Phe、Trp、Pal、His、β−Nal、3−ピリジル−Ala、4−ピリジル−Ala、2,4−ジクロロ−Phe、ペンタフルオロ−Phe、p−Z−Phe、及びo−Z−Phe(Zは、Me、Cl、Br、F、OH、OMe、及びNO2からなる群から選択される)からなる群から選択されるポリペプチド。
- 請求項1記載のポリペプチドであって、AA4がL−Trpであるポリペプチド。
- 請求項1記載のポリペプチドであって、AA2がD−Cysであるポリペプチド。
- 請求項5記載のポリペプチドであって、AA3がPheであり、AA4がTrpであり、AA5がLysであり、AA6がThrであり、AA7がValであり、そしてAA1がCpaであるポリペプチド。
- 請求項6記載のポリペプチドであり、前記ポリペプチドが、式Cpa−c[D−Cys−Phe−Trp−Lys−Thr−Cys]−Val−NH2(配列番号:5)を有するポリペプチド。
- ポリペプチドもしくはその変異体、または前記ポリペプチドもしくは変異体の薬学的に許容できる塩、及び薬学的に許容できる担体を含んでなる医薬組成物であって、前記ポリペプチドが、式:
(R1)a−AA1−シクロ[AA2−AA3−AA4−AA5−AA6−Cys]−AA7−R2
(式中、
AA1は、芳香族アミノ酸のL異性体であり;
AA2は、CysのLまたはD異性体であり;
AA3は、芳香族アミノ酸のL異性体であり;
AA4は、TrpのLまたはD異性体であり;
AA5は、Lys、N−Me−Lys、またはOrnのLまたはD異性体であり;
AA6は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nleまたは芳香族アミノ酸のLまたはD異性体であり;
AA7は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nleまたは芳香族アミノ酸のLまたはD異性体であり;
R1は、H、低級アルキル、低級アルカノイル、または低級アシルであって;aは、1または2であり;そして、R2は、OH、OR3、N(R3)2、またはNHR3であり、ここでR3は、H、低級アルキル、またはアリールアルキルである。)
を有する医薬組成物。但し、前記ペプチドはCpa−c[D−Cys−Pal−D−Trp−Lys−Val−Cys]−Cpa−NH2ではない。 - 請求項8記載の医薬組成物であって、AA3が、Phe、Trp、Pal、His、β−Nal、3−ピリジル−Ala、4−ピリジル−Ala、2,4−ジクロロ−Phe、ペンタフルオロ−Phe、p−Z−Phe、及びo−Z−Phe(Zは、Me、Cl、Br、F、OH、OMe、及びNO2からなる群から選択される)からなる群から選択される医薬組成物。
- 請求項8記載の医薬組成物であって、AA4がL−Trpである医薬組成物。
- 請求項8記載の医薬組成物であって、AA2がD−Cysである医薬組成物。
- 請求項12記載の医薬組成物であって、AA3がPheであり、AA4がTrpであり、AA5がLysであり、AA6がThrであり、AA7がValであり、そしてAA1がCpaである医薬組成物。
- 請求項13記載の医薬組成物であって、前記ポリペプチドが、式Cpa−c[D−Cys−Phe−Trp−Lys−Thr−Cys]−Val−NH2(配列番号:5)を有する医薬組成物。
- 請求項8記載の医薬組成物であって、前記担体が、生理食塩水、緩衝化された生理食塩水、デキストロース、水、グリセロール、エタノール、及びそれらの組み合わせからなる群から選択される医薬組成物。
- 過剰のウロテンシン−II活性によって特徴付けられる異常な状態を予防または治療する方法であって、前記方法が、治療学的に有効な量のポリペプチドまたはその変異体または薬学的に許容できるそれらの塩を対象に投与することを含んでなり、前記ポリペプチドが、式:
(R1)a−AA1−シクロ[AA2−AA3−AA4−AA5−AA6−Cys]−AA7−R2
(式中、
AA1は、芳香族アミノ酸のL異性体であり;
AA2は、CysのLまたはD異性体であり;
AA3は、芳香族アミノ酸のL異性体であり;
AA4は、TrpのLまたはD異性体であり;
AA5は、Lys、N−Me−Lys、またはOrnのLまたはD異性体であり;
AA6は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nle、または芳香族アミノ酸のLまたはD異性体であり;
AA7は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nle、または芳香族アミノ酸のLまたはD異性体であり;
R1は、H、低級アルキル、低級アルカノイル、または低級アシルであって;aは、1または2であり;そして、R2は、OH、OR3、N(R3)2、またはNHR3であり、ここで、R3は、H、低級アルキル、またはアリールアルキルである)
を有する方法。 - 請求項16記載の方法であって、前記状態が、虚血性心疾患、鬱血性心不全、門脈圧亢進症、静脈瘤出血、低血圧、狭心症、心筋梗塞、潰瘍、不安症、精神分裂症、躁鬱病、譫妄状態、痴呆症、精神遅滞症、及びジスキネジーからなる群から選択される方法。
- 請求項17記載の方法であって、前記状態が虚血性心疾患である方法。
- 請求項17記載の方法であって、前記状態が鬱血性心不全である方法。
- 請求項17記載の方法であって、前記状態が門脈圧亢進症である方法。
- 請求項17記載の方法であって、前記状態が静脈瑠出血である方法。
- ウロテンシン−II(U−II)ペプチドの作用をモジュレートする方法であって、前記方法が、ポリペプチドまたはその変異体または薬学的に許容できるそれらの塩を対象に投与することを含んでなり、前記ポリペプチドが、式:
(R1)a−AA1−シクロ[AA2−AA3−AA4−AA5−AA6−Cys]−AA7−R2
(式中、
AA1は、芳香族アミノ酸のL異性体であり;
AA2は、CysのLまたはD異性体であり;
AA3は、芳香族アミノ酸のL異性体であり;
AA4は、TrpのLまたはD異性体であり;
AA5は、Lys、N−Me−Lys、またはOrnのLまたはD異性体であり;
AA6は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nle、または芳香族アミノ酸のLまたはD異性体であり;
AA7は、Val、Thr、Leu、Ile、tert−Leu、Abu、Nle、または芳香族アミノ酸のLまたはD異性体であり;
R1は、H、低級アルキル、低級アルカノイル、または低級アシルであって;aは、1または2であり;そして、R2は、OH、OR3、N(R3)2、またはNHR3であって、ここで、R3は、H、低級アルキル、またはアリ−ルアルキルである。)
を有する方法。 - 請求項22記載の方法であって、前記モジュレートが、前記U−IIペプチドの効果を低下させることを含んでなる方法。
- ウロテンシンIIアゴニストポリペプチドまたはその変異体であって、前記ポリペプチドが式:Asp−c[Cys−Phe−Trp−Lys−Tyr−Cys]−Val−OH(配列番号:3)を有するポリペプチドまたはそのその変異体。
- ウロテンシン−II(U−II)ペプチドの作用をモジュレートする方法であって、前記方法が請求項24のポリペプチドを対象に投与することを含んでなる方法。
- 請求項25記載の方法であって、前記モジュレートが、前記U−IIペプチドの作用を高めることを含んでなる方法。
- ウロテンシン−II活性の過小発現により特徴付けられる異常な状態を予防または治療する方法であって、前記方法が、治療学的に有効な量の請求項24のポリペプチドを対象に投与することを含んでなる方法。
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US6262229B1 (en) * | 1996-12-04 | 2001-07-17 | Biomeasure Incorporated | Somatostatin antagonists |
US6159700A (en) * | 1997-01-27 | 2000-12-12 | Smithkline Beecham Corporation | Method of finding agonist and antagonist to human and rat GPR14 |
FR2786489B1 (fr) * | 1998-11-26 | 2002-12-27 | Inst Nat Sante Rech Med | Urotensines ii de mammiferes et leurs appications |
JP2003527341A (ja) * | 1999-11-29 | 2003-09-16 | スミスクライン・ビーチャム・コーポレイション | ウロテンシン−ii類似体 |
ES2306766T3 (es) * | 2001-03-08 | 2008-11-16 | The Administrators Of The Tulane Educational Fund | Antagonistas de somatostatina. |
IL158051A0 (en) * | 2001-04-09 | 2004-03-28 | Univ Tulane | Somatostatin agonists |
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2001
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- 2001-10-19 MX MXPA03003297A patent/MXPA03003297A/es active IP Right Grant
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- 2001-10-19 JP JP2002536313A patent/JP4081369B2/ja not_active Expired - Fee Related
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- 2001-10-19 AU AU2002232903A patent/AU2002232903B2/en not_active Ceased
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- 2001-10-19 DK DK01987763T patent/DK1355940T3/da active
- 2001-10-19 EP EP01987763A patent/EP1355940B1/en not_active Expired - Lifetime
- 2001-10-19 US US10/399,542 patent/US7241737B2/en not_active Expired - Fee Related
- 2001-10-19 CA CA002425804A patent/CA2425804A1/en not_active Abandoned
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- 2001-10-19 KR KR1020037004970A patent/KR100707408B1/ko not_active IP Right Cessation
- 2001-10-19 KR KR1020067014787A patent/KR100795427B1/ko not_active IP Right Cessation
- 2001-10-19 RU RU2003114734/04A patent/RU2263679C2/ru not_active IP Right Cessation
- 2001-10-19 KR KR1020067014786A patent/KR100820896B1/ko not_active IP Right Cessation
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