JP2012524816A - 心血管疾患の治療のための組成物及び方法 - Google Patents
心血管疾患の治療のための組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、参照により本明細書に組み込まれている、2009年4月23日に出願した米国仮出願第61/214,425号の利益を主張するものである。
本発明は、心血管疾患を治療するための化合物および方法に関する。詳細には、本発明は、ミエロペルオキシダーゼ(MPO)酵素活性の低減に使用することができ、したがって、高血圧症、アテローム性動脈硬化症、冠動脈性心疾患、狭心症、脳卒中および心筋梗塞症などの心血管疾患の治療に有用であり得る、メチレンジオキシフェニルフェルレート及フェルリルプロリンを含むオルトメトキシフェノール系化合物ならびにそれらの誘導体に関する。さらに、本発明は、治療を必要としている対象における、低比重および高比重リポタンパク質酸化の低減、血管拡張の増加または改善、粥腫(plaque)不安定化の低減、高密度リポタンパク質の炎症促進性の低減およびコレステロール逆輸送の促進へのオルトメトキシフェノール系化合物およびそれらの誘導体の使用に関する。
米国などの国々において、高血圧症、脳卒中、および心血管系に関連する他の疾患は、広範囲に見られる罹病率および死亡率の主な原因であり、世界中の非常に多数の人々に大きな苦難および経済的損失をもたらしている。例えば、世界中で約6億人の人々が高血圧症に罹患しており、そのうち約5000万人が米国に居住していると推定された。さらにまた、高血圧症単独でも、2007年に米国だけで664億ドルの歳出を招いたと推定された。
本発明によれば、心血管疾患を治療するための化合物および方法が提供される。詳細には、本発明は、ミエロペルオキシダーゼ(MPO)酵素活性を十分に阻害するまたは他の方法で低減させることができるオルトメトキシフェノール系化合物およびそれらの誘導体を提供する。これらの化合物は、高血圧症、アテローム性動脈硬化症、冠動脈性心疾患、狭心症、脳卒中および心筋梗塞症を含む種々の心血管疾患の治療に有用である。一部の実施形態において、これらの化合物をこのような治療を必要としている対象に投与して、低比重リポタンパク質酸化を低減し、血管拡張を改善しまたは粥腫不安定化を低減することができる。
Parthasarathy Sら Methods Mol. Biol.2010.610、403−17およびそこに記載された参考文献を参照のこと)。その場合には、LDLの酸化されやすさを示す酸化の遅延時間は、分光光度計を用いて測定することができ、対象に生じているLDL酸化量を把握できる。
メチレンジオキシフェニルフェルレート(式(II))を合成するために、フェルラ酸、メチレンジオキシフェノール、ジメチルアミノピリジン(DMAP)、トリエチルアミン(TEA)およびN−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミドヒドロクロリド(EDCI)を含む、下記の合成手順のための化学物質および試薬を、最初にSigma−Aldrich Co.(St.Louis、MO)から購入した。
フェルリルプロリン(式(XVI))を合成するために、フェルラ酸、L−プロリンメチルエステルヒドロクロリド、ジメチルアミノピリジン(DMAP)およびジシクロヘキシルカルボジイミド(DCC)含む、下記の合成手順のための化学物質および試薬を、最初にSigma−Aldrich Co.(St.Louis、MO)から購入した。フェルリルプロリンの合成は、フェルラ酸とプロリンのメチルエステルとのカップリング反応およびそれに続く、エステルの塩基触媒加水分解による遊離カルボン酸の再生を用いて実施した。反応全体を窒素雰囲気下で実施した。
本発明の化合物が種々の濃度でミエロペルオキシダーゼ(MPO)活性を阻害するかどうかを判定するために、MPOアッセイにおいて基質としてテトラメチルベンジジン(TMB)を用いた。TMBを用いたのは、TMBがグアイアコールよりも感受性でありおよび色が安定であるためである。典型的には、反応混合物(200μl)は、ヒトMPO(Sigma−Aldrich、St.Louis、MO)20mU、H2O2 400nmol、TMB 1.6μmolおよび種々の濃度のメチレンジオキシフェニルフェルレート(式(II))またはフェルリルプロリン(式XVI))を含んでいた。
本出願で開示される化合物の低比重リポタンパク質(LDL)酸化に対する作用を判定するために、標準的なLDL酸化反応を、メチレンジオキシフェニルフェルレート(FMDP、式(II))およびフェルリルプロリン(式(XVI))の存在下で実施した。簡潔には、LDLのインビトロ酸化反応を室温においてリン酸カリウム緩衝液(pH7.4)中で実施した。反応混合物は、LDLタンパク質100μgおよび5μM Cu(II)を含んでおり、最終容量が1mLであった、LDLの酸化は、分光光度計を用いて合計300分間、234nmの共役ジエンの形成を測定することによって追跡した。次に、Cu(II)誘発LDL酸化の経時変化を行った。メチレンジオキシフェニルフェルレート濃度10μMおよび25μMにおいて、LDL酸化の完全な阻害が観察された(図6)。同一条件下で、フェルリルプロリンは酸化促進剤として作用し、遅延時間を短縮した(図6)。フェルリルプロリン10μMおよび25μMの存在下におけるLDL酸化の増加は、LDLの酸化促進剤として作用するCu(II)−フェルリルプロリン錯体の形成によるものであった。阻害薬の不存在下ならびに10μMおよび25μMのメチレンジオキシフェニルフェルレートおよびフェルリルプロリンの存在下における、Cu(II)媒介酸化によるLDL脂質の酸化を、酸化を200分間監視することによって実施した。
本発明の化合物がシトクロムcの還元を効果的に阻害できるかどうかを判定するために、キサンチン/キサンチンオキシダーゼによって発生させたスーパーオキシドラジカルによってシトクロムcを還元し、シトクロム還元生成物を分光光度計で549nmにおいて観察した。反応混合物は、5mMヒポキサンチン250μL(最終濃度1.25mM)、緩衝液中シトクロムc 100μL、キサンチンオキシダーゼ酵素10μLおよび種々の濃度の阻害薬を含んでいた。燐酸塩緩衝液を用いて最終容量を1mLとした。5回の測定によって500から600nmの間の波長を走査することによって、酸化を監視した。走査サイクル時間は30秒とした。結果から、フェルリルプロリンは反応を阻害する(図7)が、メチレンジオキシフェニルフェルレートは阻害をそれほど引き起こさないことが明らかになった。このことは、前記化合物の、MPO阻害に対する特異性を示している。
クロロタウリンは、H2O2による塩化物のMPO媒介2電子酸化によって形成される塩素化酸化剤、次亜塩素酸(HOCl)によるタウリンの酸化によって形成される。本発明の化合物がクロロタウリンの形成を阻害できるかどうかを判定するために、リン酸ナトリウム緩衝液中に150mMタウリン50μL、種々の濃度のメチレンジオキシフェニルフェルレート(式(II))またはフェルリルプロリン(式(XVI))および次亜塩素酸250μLを含む反応混合物を生成した。混合物を37℃で10分間インキュベートし、続いて40mMチオニトロ安息香酸(TNB)60μLを添加した。全溶液を1.5mLとし、紫外可視分光光度計を用いて412nmにおいて吸収を測定した。結果から、メチレンジオキシフェニルフェルレートは反応を阻害する(図8)が、フェルリルプロリンは阻害を引き起こさないことがわかった。さらに、これらの2つの化合物はクロロタウリン酸化に対して異なる反応をするが、MPO阻害に対する特異性を示すように思われる。
MPOは種々の基質に作用することが知られている。したがって、前記実験において、メチレンジオキシフェニルフェルレート(式(II))およびフェルリルプロリン(式(XVI))がMPO基質として作用しおよび添加基質からの生成物の形成を競合的にマスクしていることは理論的にはあり得ると考えられた。しかし、MPOを用いても用いなくても、メチレンジオキシフェニルフェルレートおよびフェルリルプロリンの200から700nmの間の紫外可視スペクトルの測定は生成物を示さなかった(図9および10)。これらの実験において、酢酸ナトリウム緩衝液720μL、100mM H2O2 100μL、MPO酵素100μLを含み、本発明の化合物が添加された反応混合物を生成し、総容量を1mLとした。しかし、この反応混合物の分析時に、反応混合物がMPO基質を含まずに阻害薬のみを含む場合でさえ、有色生成物は認められなかった。この知見を確かなものにするために、MPOアッセイ溶液および阻害薬を用いて薄層クロマトグラフィー(TLC)を行い(50%酢酸エチル:ヘキサン)、ヨウ素チャンバー中でスポット同定を行った。TLC実験はMPO反応中に生成物の形成を示さなかった。これは、メチレンジオキシフェニルフェルレートおよびフェルリルプロリンはMPO基質として作用せず、むしろMPOの阻害薬と特徴付けられるべきであることを示している。
Claims (45)
- 請求項1の化合物および医薬として許容され得るビヒクル、担体または賦形剤を含む医薬組成物。
- 請求項16の化合物および医薬として許容され得るビヒクル、担体または賦形剤を含む医薬組成物。
- ミエロペルオキシダーゼ酵素活性の低減方法であって、式(I):
R1は、OCH3、OHおよびOCH2CH3からなる群から選択され、
R2は、OHおよびOCH3からなる群から選択され、ならびに、
R3は、
式(XV):
R1は、OCH3、OCH2CH3およびCONHNH2からなる群から選択され、
R2は、OHおよびNH2からなる群から選択され、ならびに、
R3は、
式(XXVII):
からなる群から選択される化合物またはその医薬として許容され得る塩もしくは溶媒和物の有効量をミエロペルオキシダーゼ酵素と接触させることを含む、方法。 - 心血管疾患の治療方法であって、式(I):
R1は、OCH3、OHおよびOCH2CH3からなる群から選択され、
R2は、OHおよびOCH3からなる群から選択され、ならびに、
R3は、
式(XV):
R1は、OCH3、OCH2CH3およびCONHNH2からなる群から選択され、
R2は、OHおよびNH2からなる群から選択され、ならびに、
R3は、
式(XXVII):
からなる群から選択される化合物またはその医薬として許容され得る塩もしくは溶媒和物の有効量を、心血管疾患の治療を必要としている対象に投与することを含む、方法。 - 心血管疾患が、高血圧症、アテローム性動脈硬化症、冠動脈性心疾患、狭心症、脳卒中および心筋梗塞からなる群から選択される、請求項40の方法。
- アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体遮断薬、スタチン、抗炎症薬、脂肪酸の吸収を阻害する薬剤、抗血小板薬、抗凝血薬またはそれらの組み合わせの有効量を対象に投与することをさらに含む、請求項40の方法。
- 低比重リポタンパク質酸化の低減方法であって、式(I):
R1は、OCH3、OHおよびOCH2CH3からなる群から選択され、
R2は、OHおよびOCH3からなる群から選択され、ならびに、
R3は、
式(XV):
R1は、OCH3、OCH2CH3およびCONHNH2からなる群から選択され、
R2は、OHおよびNH2からなる群から選択され、ならびに、
R3は、
式(XXVII):
からなる群から選択される化合物またはその医薬として許容され得る塩もしくは溶媒和物の有効量を、低比重リポタンパク質酸化の低減を必要としている対象に投与することを含む、方法。 - 血管拡張の増加方法であって、式(I):
R1は、OCH3、OHおよびOCH2CH3からなる群から選択され、
R2は、OHおよびOCH3からなる群から選択され、ならびに、
R3は、
式(XV):
R1は、OCH3、OCH2CH3およびCONHNH2からなる群から選択され、
R2は、OHおよびNH2からなる群から選択され、ならびに、
R3は、
式(XXVII):
からなる群から選択される化合物またはその医薬として許容され得る塩もしくは溶媒和物の有効量を、血管拡張の増加を必要としている対象に投与することを含む、方法。 - 粥腫不安定化の低減方法であって、式(I):
R1は、OCH3、OHおよびOCH2CH3からなる群から選択され、
R2は、OHおよびOCH3からなる群から選択され、ならびに、
R3は、
式(XV):
R1は、OCH3、OCH2CH3およびCONHNH2からなる群から選択され、
R2は、OHおよびNH2からなる群から選択され、ならびに、
R3は、
式(XXVII):
からなる群から選択される化合物またはその医薬として許容され得る塩もしくは溶媒和物の有効量を、粥腫不安定化の低減を必要としている対象に投与することを含む、方法。
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US8958867B2 (en) * | 2011-08-29 | 2015-02-17 | Infraredx, Inc. | Detection of lipid core plaque cap thickness |
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US10776654B2 (en) | 2015-03-10 | 2020-09-15 | Infraredx, Inc. | Assessment of lipid core plaque integrity |
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US11241406B2 (en) * | 2015-08-28 | 2022-02-08 | Nature's Sunshine Products, Inc. | Compositions and methods for acutley raising nitric oxide levels |
US10767136B2 (en) * | 2015-11-13 | 2020-09-08 | Firmenich Sa | Pro-fragrance compounds |
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