JP2015529206A - Gapdhカスケードインヒビター化合物ならびに使用の方法および精神病を含むストレス誘導障害の処置 - Google Patents
Gapdhカスケードインヒビター化合物ならびに使用の方法および精神病を含むストレス誘導障害の処置 Download PDFInfo
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Abstract
Description
本出願は、2012年8月25日付け出願の米国特許仮出願第61/693266号の利益を請求し、それをここに参照することによりすべての目的についてまるでここに記載されているかのように組み込む。
適切な環境刺激は器官および生体の恒常性を維持するために必要とされるが、過剰なストレス要因はそのような恒常性を崩壊させる。基礎となるメカニズムは、核因子および遺伝子転写に関係し、そこではヒストンアセチルトランスフェラーゼ(HATs)が本質的な役割を果たす。酵素p300は、心臓および脳の器官機能の維持に必須な代表的なHATであり、その一方でそれはまた病因に関わる。それゆえ、p300の活性が、生理機能または病態生理を媒介するために、どのようにして、たとえば、ストレスなどのような環境および内因子によって影響されるかは、本質的な生物学的問題である。
本発明者らは、推定上のドミナントネガティブ(優性阻害)DISC1(DN-DISC1)を発現するトランスジェニックマウスの使用により神経精神病学の病気のためのモデルの前頭前野(前頭前皮質)において研究を行った。DN-DISC1のマウスでは、酸化ストレスの顕著なレベルが前頭前野で検出されたが、線条体ではそうでなかった。これらのマウスはまた、より一層多量のGAPDH-Siah1結合、酸化ストレスへの曝露下で活性化されるタンパク質-タンパク質相互作用を示した。
一以上の実施形態によれば、本発明は、新規化合物、および、哺乳動物に、薬物デプレニルの構造的類似体である様々な化合物が含まれる製薬上組成物を施すことを含む、哺乳動物の細胞におけるGAPDH-Siah1結合の抑制およびp300の活性化の方法を提供する。
である、式Iの化合物を提供する。
例1
例2
例3
例4
例5
例6
例7
例8
例9
例10
例11
Claims (18)
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-
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- 器官は脳である、請求項3の製薬上組成物。
- ストレス誘導障害は、気分障害、統合失調症、自閉症および嗜癖からなる群より選ばれる、請求項3または4のいずれかの製薬上組成物。
- 組成物は少なくとも一種の追加の治療上組成物を含む、請求項3ないし5のいずれかの製薬上組成物。
- 少なくとも一種の追加の治療上組成物は、抗うつ剤、複素環系抗うつ剤、モノアミンオキシダーゼインヒビター、選択的セロトニン再取込みインヒビター、三環系抗うつ剤、抗躁病剤、抗精神病剤、フェノチアジン抗精神病剤、不安緩解剤、鎮静剤、および催眠剤、バルビツール酸塩鎮静剤および催眠剤、ベンゾジアゼピン系抗不安剤、鎮静剤、および催眠剤、および精神興奮剤のような向精神剤からなる群より選ばれる、請求項6の製薬上組成物。
- 器官は心臓である、請求項3の製薬上組成物。
- ストレス誘導障害は心肥大または心筋症からなる群より選ばれる、請求項3または8のいずれかの製薬上組成物。
- 組成物は少なくとも一種の追加の治療上組成物を含む、請求項8または9のいずれかの製薬上組成物。
- 少なくとも一種の追加の治療上組成物は、αブロッカー交感神経遮断剤、交感神経遮断剤、交感神経興奮剤、およびアドレナリンアゴニスト交感神経様作用薬剤;心血管系薬剤で、抗狭心症剤、抗狭心症剤、カルシウムチャネルブロッカー抗狭心症剤、硝酸抗狭心症剤、抗不整脈剤、強心配糖体抗不整脈剤、クラスI抗不整脈剤、クラス抗不整脈剤、クラス抗不整脈剤、クラスIV抗不整脈剤、抗高血圧剤、αブロッカー抗高血圧剤、アンジオテンシン変換酵素インヒビター(ACEインヒビター)抗高血圧剤、βブロッカー抗高血圧剤、カルシウムチャネルブロッカー抗高血圧剤、中枢作用性アドレナリン性抗抗高血圧剤、抗高血圧利尿剤、末梢血管拡張抗高血圧剤、抗高脂血症剤、胆汁酸金属イオン封鎖抗高脂血症剤、還元酵素インヒビター抗高脂血症剤、循環作用剤、強心配糖体循環作用剤、血栓溶解剤、アンジオテンシンII受容体ブロッカー、ジゴキシン、ジギトキシン、利尿剤、およびアルドステロンアンタゴニストのようなものからなる群より選ばれる、請求項6の製薬上組成物。
- 化合物は、
- 化合物は、
である、請求項1ないし12のいずれかの方法。 -
- 化合物は、
である、式Iの化合物。 - 式II
- 化合物は、
である、式IIの化合物。 - 式I
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Application Number | Priority Date | Filing Date | Title |
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US201261693266P | 2012-08-25 | 2012-08-25 | |
US61/693,266 | 2012-08-25 | ||
PCT/US2013/055524 WO2014035707A1 (en) | 2012-08-25 | 2013-08-19 | Gapdh cascade inhibitor compounds and methods of use and treatment of stress induced disorders including mental illness |
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JP2015529206A true JP2015529206A (ja) | 2015-10-05 |
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US (2) | US20150218103A1 (ja) |
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Cited By (1)
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KR20190065111A (ko) * | 2017-12-01 | 2019-06-11 | 포항공과대학교 산학협력단 | Disc1 단백질 또는 이를 암호화하는 유전자를 포함하는, 스트레스성 질환의 예방 또는 치료용 약학적 조성물 |
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JP2018530322A (ja) * | 2015-10-06 | 2018-10-18 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 治療用ペプチド |
Citations (1)
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JP2004519440A (ja) * | 2000-12-18 | 2004-07-02 | ノバルティス アクチエンゲゼルシャフト | アムロジピンとベナゼプリル/ベナゼプリラートの治療上の組み合せ |
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US6503502B1 (en) | 1995-12-20 | 2003-01-07 | Société Molecular Engines Laboratories a French Société anonyme | Nucleotide sequences, proteins, drugs and diagnostic agents of use in treating cancer |
FR2820757A1 (fr) | 2001-02-13 | 2002-08-16 | Molecular Engines Lab | Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicamments |
JP2003093066A (ja) | 2001-09-21 | 2003-04-02 | Univ Tokyo | 癌細胞の増殖および細胞死を制御する方法 |
WO2003097835A2 (en) | 2002-05-16 | 2003-11-27 | Molecular Engines Laboratories | Pharmaceutical compositions for the treatment of cancer |
JP4662914B2 (ja) * | 2003-02-04 | 2011-03-30 | エフ.ホフマン−ラ ロシュ アーゲー | ガンマ−セクレターゼ阻害剤としてのマロンアミド誘導体 |
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CA2577752A1 (en) | 2004-08-20 | 2006-03-02 | The Regents Of The University Of Michigan | Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
JP5218051B2 (ja) * | 2005-10-26 | 2013-06-26 | アステラス製薬株式会社 | 新規環状ペプチド化合物 |
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- 2013-08-19 WO PCT/US2013/055524 patent/WO2014035707A1/en active Application Filing
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JP2004519440A (ja) * | 2000-12-18 | 2004-07-02 | ノバルティス アクチエンゲゼルシャフト | アムロジピンとベナゼプリル/ベナゼプリラートの治療上の組み合せ |
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CHEM.PHARM.BULL., vol. 48(1), JPN6017044862, 2000, pages 91 - 98 * |
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 10, JPN6017044864, 2009, pages 4034 - 4043 * |
NEUROTOXICITY RESEARCH, vol. 16(4), JPN6017015013, 2009, pages 390 - 407 * |
実験医学, vol. 30, no. 13, JPN6017015014, 1 August 2012 (2012-08-01), pages 2068 - 2071 * |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20190065111A (ko) * | 2017-12-01 | 2019-06-11 | 포항공과대학교 산학협력단 | Disc1 단백질 또는 이를 암호화하는 유전자를 포함하는, 스트레스성 질환의 예방 또는 치료용 약학적 조성물 |
KR102084767B1 (ko) * | 2017-12-01 | 2020-03-04 | 포항공과대학교 산학협력단 | Disc1 단백질 또는 이를 암호화하는 유전자를 포함하는, 스트레스성 질환의 예방 또는 치료용 약학적 조성물 |
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WO2014035707A1 (en) | 2014-03-06 |
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US10292980B2 (en) | 2019-05-21 |
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