JP2020527133A - 心臓代謝の効率を高めるための組成物および方法 - Google Patents
心臓代謝の効率を高めるための組成物および方法 Download PDFInfo
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- JP2020527133A JP2020527133A JP2019571473A JP2019571473A JP2020527133A JP 2020527133 A JP2020527133 A JP 2020527133A JP 2019571473 A JP2019571473 A JP 2019571473A JP 2019571473 A JP2019571473 A JP 2019571473A JP 2020527133 A JP2020527133 A JP 2020527133A
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- C07D213/60—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
本出願は、心臓代謝の効率を高めるための組成物および方法に関する。
A−L−B (I)
によって表され、Aが、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、Lがリンカーであり、Bが、ミトコンドリア呼吸を促進する化合物である、化合物を含む。
式中、R1、R2、およびR3は、独立に、Hまたは(C1〜C4)アルキル基であり、R4およびR8は、一緒になって、=O、−O(CH2)mO−、もしくは−(CH2)m−であり、m=2〜4であり、またはR4は、Hであり、R8は、H、OR14、SR14、もしくは(CH2CH2O)nHであり、R14は、Hまたは(C1〜C4)アルキル基であり、n=1〜15であり、R9、R10、R12、およびR13は、独立に、Hまたは(CH2CH2O)zHであり、z=1〜6であり、R11は、ミトコンドリア呼吸を促進する化合物を含む。
A−C (VII)
によって表され、Aが、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、Cが、NAD+前駆体分子である、化合物を含む。AとCは、共有結合的に連結されていてよい。
A−L−C (VIII)
によって表され、Aが、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、Lがリンカーであり、Cが、NAD+前駆体分子である、化合物を含む。Aは、Lに共有結合的に連結されていてよく、Lは、Cに共有結合的に連結されていてよい。
A−L−B (I)
によって表され、Aが、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、Lがリンカーであり、Bが、ミトコンドリア呼吸を促進する化合物である、化合物である。
式中、R1、R2、およびR3は、独立に、Hまたは(C1〜C4)アルキル基であり、R4およびR5は、一緒になって、=O、−O(CH2)mO−、もしくは−(CH2)m−であり、m=2〜4であり、またはR4は、Hであり、R5は、OR14、SR14、もしくは(CH2CH2O)nHであり、R14は、Hまたは(C1〜C4)アルキル基であり、n=1〜15であり、R6は、1つまたは複数の環位置においてヘテロ原子で必要に応じて置換されている単環または多環構造であり、各環位置は、1つまたは複数の置換基を必要に応じて含む。
式中、R1、R2、およびR3は、独立に、Hまたは(C1〜C4)アルキル基であり、R4およびR8は、一緒になって、=O、−O(CH2)mO−、もしくは−(CH2)m−であり、m=2〜4であり、またはR4は、Hであり、R8は、H、OR14、SR14、もしくは(CH2CH2O)nHであり、R14は、Hまたは(C1〜C4)アルキル基であり、n=1〜15であり、R9、R10、R12、およびR13は、独立に、Hまたは(CH2CH2O)zHであり、z=1〜15であり、R11は、上で式(I)の成分Bに関して記載したような、ミトコンドリア呼吸を促進する化合物を含む。R11は、上で式(I)の成分Lに関して記載したようなリンカーを含んでもよい。
A−C (VII)
によって表され、Aが、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、Cが、NAD+前駆体分子である、化合物も提供する。AとCは、共有結合的に連結されていてよい。
A−L−C (VIII)
によって表され、Aが、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、Lがリンカーであり、Cが、NAD+前駆体分子である、化合物も提供する。Aは、Lに共有結合的に連結されていてよく、Lは、Cに共有結合的に連結されていてよい。
ミトコンドリア機能に対する本発明の化合物の効果を分析した。HepG2細胞に試験化合物を投与し、リアルタイムで、XFe96フラックスアナライザー(Seahorse Biosciences)を使用して細胞外酸素レベルおよびpHを測定した。XFe技術は、固体状態センサーを使用して、酸素消費速度(OCR)と細胞外酸性化率(ECAR)の両方を同時に測定して、酸化的リン酸化(OXPHOS)と解糖に対する効果を同時に求めるものである。次いで、細胞をミトコンドリア機能の種々の阻害剤に順次曝して、細胞代謝を評価した。
細胞毒性なしで酸素消費速度(OCR)または細胞外酸性化率(ECAR)に変化を引き起こしたとき、化合物を正のミトコンドリア活性化合物として特定した。OXPHOS(OCR)と解糖(ECAR)の両方が阻害されたとき、細胞毒性を決定した。
酸素消費速度(OCR)は、細胞外媒体中の酸素含有量の測定値である。OCRの変化は、ミトコンドリア機能に対する効果を示唆し、双方向的となりうる。低下は、ミトコンドリア呼吸の阻害によるものであり、増大は、呼吸がエネルギー産生と結び付けられていない脱共役剤を示唆しうる。
一連の化合物を順次細胞に加えて、生体エネルギー論プロファイル、プロトン漏出などのパラメーターに対する試験化合物の効果、および予備容量を評価する。これを使用して、ミトコンドリア毒性の考えられる機序の理解を助けることができる。次の化合物:(1)オリゴマイシン、(2)FCCP、および(3)ロテノンおよびアンチマイシンAを順に加えた。
電子伝達鎖阻害剤とは、適応応答としての解糖の増加を引き起こす(たとえば、OCRを低下させ、ECARを増大させる)、ミトコンドリア呼吸の阻害剤である。
冠血流、心機能、および梗塞サイズに対する組成物の効果を分析した。
本発明の化合物には、2−(4−(2,3,4−トリメトキシベンジル)ピペラジン−1−イル)エタン−1−オール(本明細書ではCV8814と呼ぶ)および2−(4−(2,3,4−トリメトキシベンジル)ピペラジン−1−イル)エチルニコチネート(本明細書ではCV−8972と呼ぶ)が含まれる。これらの化合物は、以下のスキームに従って合成することができる。
種々の化合物の代謝をイヌにおいて分析した。
CV−8814が種々の酵素の活性に及ぼす影響を、in vitroアッセイにおいて分析した。公開された文献に基づき各酵素用に最適化した時間、温度、基質、および緩衝液の条件を使用して、10μMのCV−8814の存在下で酵素活性をアッセイした。50%またはそれより大きい阻害は、以下の酵素のいずれについても観察されなかった。ATPアーゼ、Na+/K+、ブタ心臓;コリンエステラーゼ、アセチル、ACES、ヒト;シクロオキシゲナーゼCOX−1、ヒト;シクロオキシゲナーゼCOX−2、ヒト;モノアミンオキシダーゼMAO−A、ヒト;モノアミンオキシダーゼMAO−B、ヒト;ペプチダーゼ、アンジオテンシン変換酵素、ウサギ;ペプチダーゼ、CTSG(カテプシンG)、ヒト;ホスホジエステラーゼPDE3、ヒト;ホスホジエステラーゼPDE4、ヒト;タンパク質セリン/スレオニンキナーゼ、PKC、非選択的、ラット;タンパク質チロシンキナーゼ、インスリン受容体、ヒト;タンパク質チロシンキナーゼ、LCK、ヒト;アデノシンA1、ヒト;アデノシンA2A、ヒト;アドレナリンα1A、ラット;アドレナリンα1B、ラット;アドレナリンα1D、ヒト;アドレナリンα2A、ヒト;アドレナリンα2B、ヒト;アドレナリンβ1、ヒト;アドレナリンβ2、ヒト;アンドロゲン(テストステロン)、ヒト;アンジオテンシンAT1、ヒト;ブラジキニンB2、ヒト;L型カルシウムチャネル、ベンゾジアゼピン、ラット;L型カルシウムチャネル、ジヒドロピリジン、ラット;L型カルシウムチャネル、フェニルアルキルアミン、ラット;N型カルシウムチャネル、ラット;カンナビノイドCB1、ヒト;カンナビノイドCB2、ヒト;ケモカインCCR1、ヒト;ケモカインCXCR2(IL−8RB)、ヒト;コレシストキニンCCK1(CCKA)、ヒト;コレシストキニンCCK2(CCKB)、ヒト;ドーパミンD1、ヒト;ドーパミンD2L、ヒト;ドーパミンD2S、ヒト;エンドセリンETA、ヒト;エストロゲンERα、ヒト;GABAA、塩素イオンチャネル、TBOB、ラット;GABAA、フルニトラゼパム、中枢、ラット;GABAA、Ro−15−1788、海馬、ラット;GABAB1A、ヒト;糖質コルチコイド、ヒト;グルタメート、AMPA、ラット;グルタメート、カイネート、ラット;グルタメート、代謝調節型、mGlu5、ヒト;グルタメート、NMDA、アゴニズム、ラット;グルタメート、NMDA、グリシン、ラット;グルタメート、NMDA、フェンシクリジン、ラット;グルタメート、NMDA、ポリアミン、ラット;グリシン、ストリキニーネ感受性、ラット;ヒスタミンH1、ヒト;ヒスタミンH2、ヒト;メラノコルチンMC1、ヒト;メラノコルチンMC4、ヒト;ムスカリン性M1、ヒト;ムスカリン性M2、ヒト;ムスカリン性M3、ヒト;ムスカリン性M4、ヒト;神経ペプチドY Y1、ヒト;ニコチン性アセチルコリン、ヒト;ニコチン性アセチルコリンα1、ブンガロトキシン、ヒト;オピエートδ1(OP1、DOP)、ヒト;オピエートκ(OP2、KOP)、ヒト;オピエートμ(OP3、MOP)、ヒト;血小板活性化因子(PAF)、ヒト;カリウムチャネル[KATP]、ハムスター;カリウムチャネルhERG、ヒト;PPARγ、ヒト;プロゲステロンPR−B、ヒト;セロトニン(5−ヒドロキシトリプタミン)5−HT1A、ヒト;セロトニン(5−ヒドロキシトリプタミン)5−HT1B、ヒト;セロトニン(5−ヒドロキシトリプタミン)5−HT2A、ヒト;セロトニン(5−ヒドロキシトリプタミン)5−HT2B、ヒト;セロトニン(5−ヒドロキシトリプタミン)5−HT2C、ヒト;セロトニン(5−ヒドロキシトリプタミン)5−HT3、ヒト;ナトリウムチャネル、部位2、ラット;タキキニンNK1、ヒト;輸送体、アデノシン、モルモット;輸送体、ドーパミン(DAT)、ヒト;輸送体、GABA、ラット;輸送体、ノルエピネフリン(NET)、ヒト;輸送体、セロトニン(5−ヒドロキシトリプタミン)(SERT)、ヒト;およびバソプレシンV1A、ヒト。
CV−8972(2−(4−(2,3,4−トリメトキシベンジル)ピペラジン−1−イル)エチルニコチネートHCl塩一水和物)を調製し、分析した。バッチは、HPLCによって、99.62%純粋であると決定された。
化合物をラットに静脈内投与した後、トリメタジジンおよびCV−8814の脳対血漿比を分析した。投与溶液を、液体クロマトグラフィータンデム質量分析(LC−MS/MS)によって分析した。結果を表67に示す。
本開示全体を通して、特許、特許出願、特許公報、雑誌、書籍、論文、ウェブコンテンツなどの他の文書の参照および引用がなされている。そのような文書はすべて、すべての目的で、その全体が参照により本明細書に援用される。
本明細書で引用した科学および特許文献の参照を含む本文書の完全な内容から、当業者には、本明細書において示し、記載したものに加えて、本発明の種々の変更形態および多数のそのさらなる実施形態が明白となる。本明細書における主題は、本発明の種々の実施形態およびその均等物の中に、本発明の実施に適合させることのできる重要な情報、例証、およびガイダンスを含んでいる。
Claims (94)
- 式(VII):
A−C (VII)
によって表される化合物であって、式中、
Aは、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物を含み、
Cは、NAD+前駆体分子である、
化合物。 - CがAに共有結合的に連結されている、請求項1に記載の化合物。
- Aがエチレングリコール部分でPEG化されている、請求項2に記載の化合物。
- 前記エチレングリコール部分が、(CH2CH2O)xを含み、式中、x=1〜15である、請求項3に記載の化合物。
- 前記共有結合性連結が、前記エチレングリコール部分を介するものである、請求項4に記載の化合物。
- 前記共有結合性連結が、前記エチレングリコール部分を介するものでない、請求項4に記載の化合物。
- Aが、トリメタジジン、エトモキシル、ペルヘキシリン、PPARアゴニスト、マロニルCoA脱炭酸酵素阻害剤、およびジクロロアセテートからなる群より選択される、請求項1に記載の化合物。
- Cが、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項1に記載の化合物。
- Cがニコチン酸である、請求項8に記載の化合物。
- 前記心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物が、PEG化された形態のトリメタジジンである、請求項5に記載の化合物。
- Cが、前記PEG化された形態のトリメタジジンに共有結合的に連結されているニコチン酸である、請求項10に記載の化合物。
- 前記ニコチン酸が、前記PEG化された形態のトリメタジジンに、PEG化部分を介して共有結合的に連結されている、請求項11に記載の化合物。
- 式(X):
- 前記ニコチン酸が、前記PEG化された形態のトリメタジジンに、トリメタジジン部分を介して共有結合的に連結されている、請求項11に記載の化合物。
- Aが、ニコチン酸であるCに共有結合的に連結されているトリメタジジンである、請求項1に記載の化合物。
- 式(VIII):
A−L−C (VIII)
によって表される化合物であって、式中、
Aは、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、
Lは、リンカーであり、
Cは、NAD+前駆体分子である、
化合物。 - Aが、トリメタジジン、エトモキシル、ペルヘキシリン、PPARアゴニスト、マロニルCoA脱炭酸酵素阻害剤、およびジクロロアセテートからなる群より選択される、請求項16に記載の化合物。
- Aがトリメタジジンである、請求項17に記載の化合物。
- Cが、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項16に記載の化合物。
- Cがニコチン酸である、請求項19に記載の化合物。
- Lが、(CH2CH2O)xを含み、式中、x=1〜15である、請求項16に記載の化合物。
- Aがトリメタジジンである、請求項21に記載の化合物。
- 式(X):
- 式(VI):
A、B、C、D、E、およびF位の少なくとも1つが、−(CH2CH2O)nHで置換されており、n=1〜15である、
化合物。 - F位が置換されている、請求項24に記載の化合物。
- 式(IX):
- 式(I):
A−L−B (I)
によって表される化合物であって、式中、
Aは、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、
Lは、リンカーであり、
Bは、ミトコンドリア呼吸を促進する化合物である、
化合物。 - Aが、トリメタジジン、エトモキシル、ペルヘキシリン、PPARアゴニスト、マロニルCoA脱炭酸酵素阻害剤、およびジクロロアセテートからなる群より選択される、請求項27に記載の化合物。
- Aがトリメタジジンである、請求項28に記載の化合物。
- Bが、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項29に記載の化合物。
- Bがスクシネートである、請求項30に記載の化合物。
- Lが、(CH2CH2O)xを含み、式中、x=1〜15である、請求項27に記載の化合物。
- 前記式(I)の化合物に化学的に連結されているCをさらに含み、Cは、NAD+前駆体分子である、請求項27に記載の化合物。
- Cが、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項33に記載の化合物。
- Cがニコチン酸であり、前記式(I)の化合物が、式(II):
- 前記式(I)の化合物が、式(III):
- 式(IV):
R1、R2、およびR3は、Hおよび(C1〜C4)アルキル基からなる群より独立に選択され、
R4およびR5は、一緒になって、=O、−O(CH2)mO−、もしくは−(CH2)m−であり、m=2〜4であり、またはR4は、Hであり、R5は、OR14、SR14、もしくは(CH2CH2O)nHであり、R14は、Hまたは(C1〜C4)アルキル基であり、n=1〜15であり、
R6は、1つまたは複数の環位置においてヘテロ原子で必要に応じて置換されている単環または多環構造であり、各環位置は、1つまたは複数の置換基を必要に応じて含む、
化合物。 - R6の少なくとも1つの環位置が、ミトコンドリア呼吸を促進する化合物を含む置換基を含む、請求項37に記載の化合物。
- 前記ミトコンドリア呼吸を促進する化合物が、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項38に記載の化合物。
- 前記ミトコンドリア呼吸を促進する化合物がスクシネートである、請求項39に記載の化合物。
- 前記置換基が、(CH2CH2O)xを含み、式中、x=1〜15である、請求項38に記載の化合物。
- 前記置換基がNAD+前駆体分子を含む、請求項38に記載の化合物。
- 前記NAD+前駆体分子が、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項42に記載の化合物。
- 前記NAD+前駆体分子がニコチン酸であり、前記置換基が
- 前記置換基が
- R6が
- 式(IX)および式(XO:
- 式(V):
R1、R2、およびR3は、Hおよび(C1〜C4)アルキル基からなる群より独立に選択され、
R4およびR8は、一緒になって、=O、−O(CH2)mO−、もしくは−(CH2)m−であり、m=2〜4であり、またはR4は、Hであり、R8は、H、OR14、SR14、もしくは(CH2CH2O)nHであり、R14は、Hまたは(C1〜C4)アルキル基であり、n=115であり、
R9、R10、R12、およびR13は、Hおよび(CH2CH2O)zHからなる群より独立に選択され、z=1〜6であり、
R11は、ミトコンドリア呼吸を促進する化合物を含む、
化合物。 - 前記呼吸を促進する化合物が、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項48に記載の化合物。
- 前記呼吸を促進する化合物がスクシネートである、請求項49に記載の化合物。
- R11が、(CH2CH2O)xをさらに含み、式中、x=1〜15である、請求項48に記載の化合物。
- R11が
- R11がNAD+前駆体分子をさらに含む、請求項48に記載の化合物。
- 前記NAD+前駆体分子が、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項53に記載の化合物。
- NAD+前駆体分子がニコチン酸であり、R11が
- 被験体において心臓代謝の効率を高める方法であって、式(I):
A−L−B (I)
によって表される化合物を提供することを含み、式中、
Aは、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、
Lは、リンカーであり、
Bは、ミトコンドリア呼吸を促進する化合物である、
方法。 - Aが、トリメタジジン、エトモキシル、ペルヘキシリン、PPARアゴニスト、マロニルCoA脱炭酸酵素阻害剤、およびジクロロアセテートからなる群より選択される、請求項56に記載の方法。
- Aがトリメタジジンである、請求項57に記載の方法。
- Bが、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項58に記載の方法。
- Bがスクシネートである、請求項59に記載の方法。
- Lが、(CH2CH2O)xを含み、式中、x=1〜15である、請求項56に記載の方法。
- 前記式(I)によって表される化合物が、前記式(I)の化合物に化学的に連結されているCをさらに含み、Cは、NAD+前駆体分子である、請求項56に記載の方法。
- Cが、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項62に記載の方法。
- Cがニコチン酸であり、前記式(I)の化合物が、式(II):
- 前記式(I)の化合物が、式(III):
- 被験体において心臓代謝の効率を高める方法であって、
心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる第1の化合物、
ミトコンドリア呼吸を促進する第2の化合物、および
NAD+前駆体分子である第3の化合物
を提供することを含む、方法。 - 前記第1の化合物が、トリメタジジン、エトモキシル、ペルヘキシリン、PPARアゴニスト、マロニルCoA脱炭酸酵素阻害剤、およびジクロロアセテートからなる群より選択される、請求項66に記載の方法。
- 前記第1の化合物がトリメタジジンである、請求項67に記載の方法。
- 前記第2の化合物が、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項66に記載の方法。
- 前記第2の化合物がスクシネートである、請求項69に記載の方法。
- 前記第3の化合物が、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項66に記載の方法。
- 前記第3の化合物がニコチン酸である、請求項71に記載の方法。
- 前記第1の化合物、前記第2の化合物、および前記第3の化合物を単一組成物において提供する、請求項66に記載の方法。
- 前記第1の化合物、前記第2の化合物、および前記第3の化合物を単一組成物において提供しない、請求項66に記載の方法。
- A、B、およびCからなる群より選択される少なくとも2つを含む組成物であって、
Aは、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、
Bは、ミトコンドリア呼吸を促進する化合物であり、
Cは、NAD+前駆体分子である、
組成物。 - 前記心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物がトリメタジジンである、請求項75に記載の組成物。
- 前記ミトコンドリア呼吸を促進する化合物が、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項75に記載の組成物。
- 前記NAD+前駆体分子が、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項75に記載の組成物。
- A、B、およびCを含む、請求項75に記載の組成物。
- AおよびBを含む第1の分子と、
Cを含む第2の分子と
を含む共結晶を含む、請求項79に記載の組成物。 - Aがトリメタジジンであり、
Bがスクシネートであり、
Cがニコチンアミドである、
請求項80に記載の組成物。 - 前記第1の分子が、リンカーを介してスクシネートに共有結合的に連結されているトリメタジジンを含む、請求項81に記載の組成物。
- 前記リンカーが、(CH2CH2O)xを含み、式中、x=1〜15である、請求項82に記載の組成物。
- 被験体において、心不全、心機能不全、筋ミオパシー、ミトコンドリア機能の障害、または脂肪酸酸化の変化と関連する状態を処置する方法であって、前記方法は、式(I):
A−L−B (I)
によって表される化合物を提供することを含み、式中、
Aは、心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる化合物であり、
Lは、リンカーであり、
Bは、ミトコンドリア呼吸を促進する化合物である、
方法。 - Aが、トリメタジジン、エトモキシル、ペルヘキシリン、PPARアゴニスト、マロニルCoA脱炭酸酵素阻害剤、およびジクロロアセテートからなる群より選択される、請求項84に記載の方法。
- Aがトリメタジジンである、請求項85に記載の方法。
- Bが、スクシネート、フマレート、マレート、オキサロアセテート、シトレート、イソシトレート、α−ケトグルタレート、ピルベート、アセトン、アセト酢酸、β−ヒドロキシ酪酸、β−ケトペンタノエート、およびβ−ヒドロキシペンタノエートからなる群より選択される、請求項86に記載の方法。
- Bがスクシネートである、請求項87に記載の方法。
- Lが、(CH2CH2O)xを含み、式中、x=1〜15である、請求項84に記載の方法。
- 前記式(I)によって表される化合物が、前記式(I)の化合物に化学的に連結されているCをさらに含み、Cは、NAD+前駆体分子である、請求項84に記載の方法。
- Cが、ニコチン酸、ニコチンアミド、およびニコチンアミドリボシドからなる群より選択される、請求項90に記載の方法。
- Cがニコチン酸であり、前記式(I)の化合物が、式(II):
- 前記式(I)の化合物が、式(III):
- 被験体において、心不全、心機能不全、筋ミオパシー、ミトコンドリア機能の障害、または脂肪酸酸化の変化と関連する状態を処置する方法であって、
心臓代謝を脂肪酸酸化からグルコース酸化へとシフトさせる第1の化合物、
ミトコンドリア呼吸を促進する第2の化合物、および
NAD+前駆体分子である第3の化合物
を提供することを含む、方法。
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