JP2018535272A - 神経変性疾患の予防及び治療において使用するための化合物 - Google Patents
神経変性疾患の予防及び治療において使用するための化合物 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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Abstract
Description
a)α-シヌクレイン(α-syn)凝集の形成阻害、及び
b)リポカリン2(Lcn2/NGAL)への結合
が可能な化合物を特定する。
(i) 本発明の第一の化合物、及び
(ii) 神経変性疾患を予防又は治療するために使用される第二の化合物;
の有効量、並びに、一つ以上の薬学的に許容される助剤を含み、治療を必要とする患者に、別々に、連続で又は同時に投与するための、キットを特定する。場合により、第二の化合物は、レボドパ、ドーパミンアゴニスト、モノアミンオキシダーゼインヒビター、抗コリン作用薬グルタミン酸アンタゴニスト、カテコール-C-メチルトランスフェラーゼ(COMT)インヒビター及びDOPAデカルボキシラーゼインヒビターから成る群から選択されてよい。
(i)α-シヌクレイン(α-syn)凝集の形成阻害、及び
(ii)リポカリン2(Lcn2/NGAL)への結合
が可能な化合物の有効量を投与することを含む、神経変性疾患を治療又は予防するための方法に関する。
遊離及び結合したスルホカリックスアレーンのLcn2への結合は、Microcal ITC200 マイクロカロリメーターを使用し、ITCによって決定した。実験を、25°Cで、20mMTris(pH7.4)、50mMNaCl中で行った。参照細胞はMilli Q水を含有した。反応性細胞中でのLcn2の濃度は50μMであった。シリンジ内のスルホカリックスアレーンの濃度は500μMであった。滴定は、撹拌速度800rpmで、300秒間隔で分離された、4μLの19回連続注入で構成された。データ分析は、Origin softwareで行い、単一の結合部位が推定された。
Bi, F., Huang, C., Tong, J., Qiu, G., Huang, B., Wu, Q., et al. (2013). Reactive astrocytes secrete lcn2 to promote neuron death. Proceedings of the National Academy of Sciences of the United States of America, 110(10), 4069-4074. doi:10.1073/pnas.1218497110
Kim, B. W., et al. (2016). Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System. Journal of Neuroscience, 36(20), 5608-5622. doi:10.1523/JNEUROSCI.4261-15.2016
Lamberto, G. R., Binolfi, A., Orcellet, M. L., Bertoncini, C. W., Zweckstetter, M., Griesinger, C., & Fernandez, C. O. (2009). Structural and mechanistic basis behind the inhibitory interaction of PcTS on α-synuclein amyloid fibril formation. Proceedings of the National Academy of Sciences, 106(50), 21057-21062.
Rabl, R., Horvath, A., Breitschaedel, C., Flunkert, S., Roemer, H., & Hutter-Paier, B. (2016). Journal of Neuroscience Methods. Journal of Neuroscience Methods, 274, 125-130. doi:10.1016/j.jneumeth.2016.10.006
Claims (15)
- 神経変性疾患の予防又は治療において使用するための、
a)α-シヌクレイン(α-syn)凝集の形成阻害、及び
b)リポカリン2(Lcn2/NGAL)への結合
が可能な化合物。 - さらに、
c)酸化ストレスに対する保護効果を有する、及び/又は
d)ミトコンドリア機能障害誘発性の神経毒性に対する保護効果を有する、及び/又は
e) α-synトランスジェニック(tg)マウスにおいて、濃度依存的に運動障害を改善することができる、
請求項1に記載の化合物。 - 疾患が、シヌクレイノパチー、好ましくは、パーキンソン病、レビー小体型認知症及び多系統萎縮症から成る群から選択されるシヌクレイノパチーである、神経変性疾患の予防又は治療において使用するための、請求項1に記載の化合物。
- さらに、ニューロンの増殖を促進することができる、神経変性疾患の予防又は治療において使用するための、請求項1から3のいずれか一項に記載の化合物。
- さらに、アストロサイトの活性化の制御をすることができる及び/又は静止状態のアストロサイトから反応性アストロサイトへの転換の阻害をすることができる、神経変性疾患の予防又は治療において使用するための、請求項1から4のいずれか一項に記載の化合物。
- 化合物のLcn2/NGALへの結合部位が、その細胞内同族受容体の1つへのLcn2/NGALの結合と競合的である、神経変性疾患の予防又は治療において使用するための、請求項1から5のいずれか一項に記載の化合物。
- Lcn2/NGALの神経毒性に対して阻害効果を示す、神経変性疾患の予防又は治療において使用するための、請求項6に記載の化合物。
- 最終分化神経芽細胞腫SH-SY5Y細胞において上方制御される、Lcn2/NGAL同族細胞内受容体(SLC22A17)の結合と競合する、神経変性疾患の予防又は治療において使用するための、請求項6に記載の化合物。
- ニューロンにおけるα-syn凝集の形成阻害が、α-syn膜結合の低減並びに伝搬するα-syn二量体及び小さなオリゴマーへのアッセンブリの低減によって達成される、神経変性疾患の予防又は治療において使用するための、請求項1〜8のいずれか一項に記載の化合物。
- 最終分化神経芽細胞腫SH-SY5Y細胞において、MPP+誘導性ミトコンドリア機能障害及び酸化ストレス(H2O2)に対する保護効果を付与することによって特徴づけられる、神経変性疾患の予防又は治療において使用するための、請求項6に記載の化合物。
- α-syn単量体、α-syn二量体又は小さなα-synオリゴマーのN末端ドメインと相互作用する、神経変性疾患の予防又は治療において使用するための、請求項7又は9に記載の化合物。
- カリックスアレーン骨格を含む、神経変性疾患の予防又は治療において使用するための、請求項1〜11のいずれか一項に記載の化合物。
- スルホカリックスアレーンのナトリウム塩又はその誘導体である、神経変性疾患の予防又は治療において使用するための、請求項12に記載の化合物。
- 治療が、約0.01mg〜5.0g/kg体重の量で、化合物を患者に投与することを含み、好ましくは、化合物の投与は、静脈内投与又は経口投与である、神経変性疾患の予防又は治療において使用するための、請求項1〜13のいずれか一項に記載の化合物。
- (i)カリックスアレーン骨格を含む第一の化合物;
(ii) レボドパ、ドーパミンアゴニスト、モノアミンオキシダーゼインヒビター、抗コリン作用薬グルタミン酸アンタゴニスト、カテコール-C-メチルトランスフェラーゼ(COMT)インヒビター及びDOPAデカルボキシラーゼインヒビターから成る群から選択される第二の薬学的に活性な化合物;
の有効量;並びに
一つ以上の薬学的に許容される助剤;
を含み、治療を必要とする神経変性疾患を有する患者に対して、別々に、連続で又は同時に投与するための、キット。
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