JP6756925B2 - ヒストンデアセチラーゼの二環式阻害剤 - Google Patents
ヒストンデアセチラーゼの二環式阻害剤 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
本出願は、2017年1月11日に出願された米国仮特許出願第62/445,022号および2017年9月7日に出願された米国仮特許出願第62/555,298号の優先権を主張する。これらの各々の内容は、参照により本明細書に組み込まれる。
連邦政府による資金提供を受けた研究開発に関する声明
技術分野
2.定義
3.用途、配合および投与
実施例1
実施例2
HDAC2およびHDAC1酵素アッセイ
HDAC−Glo2基質を用いるSY5Y細胞溶解物中のHDAC2酵素阻害アッセイ
細胞培養および阻害剤処置
赤血球および骨髄CFUアッセイ
細胞
化合物
方法概要
CFC番号の統計分析
コロニーの形態学的評価
CYP阻害アッセイ
1.試験化合物および参照阻害剤(400倍)を96ウェルプレート中に準備する。
1.1.8μLの10μM試験化合物を12μLのACNに移す。
1.2.CYP3A4、CYP2D6用の個々の阻害剤スパイク溶液を調製する:8μLのDMSOストック対12μLのACN。
2.4xNADPH補因子(10mLの0.1MK緩衝液中の66.7mgのNADPH、pH7.4)を調製する。
3.4x基質(各アイソフォームにつき2mL)を、以下の表に示すように調製する(必要に応じて、氷上でHLMを添加する)。
4.0.2mg/mLのHLM溶液(990μLの0.1MK緩衝液に10μLの20mg/mL)を氷上で調製する。
5.400μLの0.2mg/mL HLMをアッセイウェルに添加し、次いで2μLの400x試験化合物を、氷上で指定されたウェルに添加する。
6.200μLの0.2mg/mLのHLMをアッセイウェルに添加し、次いで1μLの参照阻害剤溶液を、氷上で指定のウェルに添加する。
7.以下の溶液を、氷上で96ウェルアッセイプレートに加える(二重に):
7.1.0.2mg/mLのHLM溶液中の30μLの2x試験化合物および参照化合物を添加する。
7.2.15μLの4x基質溶液を加える。
8.96ウェルアッセイプレートおよびNADPH溶液を37℃で5分間プレインキュベートする。
9.15μLの予熱した8mMNADPH溶液をアッセイプレートに加えて反応を開始する。
10.アッセイプレートを37℃で、3A4では5分間、2D6では10分間、インキュベートする。
11.反応を、内部標準液を含む120μLのACNを加えて停止させる。CYP3A4の場合、内部標準液は、1‘OH−ミダゾラム−D4である(100μLの内部標準ストックを10mL ACNに添加することによって、10μMの溶液を0.1μMの最終濃度に希釈する)。CYP2D6の場合、内部標準液は、1−OH−ブフラロールマレイン酸−[D9]である(20μLの内部標準ストックを10mL ACNに添加することによって、49μM溶液を0.1μMの最終濃度に希釈する)。
12.クエンチ後、プレートをバイブレーター(IKA、MTS2/4)で10分間振盪し(600rpm/分)、次いで5594gで15分間遠心分離する(Thermo Multifugex3R)。
13.各ウェルからの50μLの上清を、LC/MS分析のために50μLの超純水(Millipore、ZMQS50F01)を含む96ウェルサンプルプレートに移す。
水性動的溶解度測定
マウスへの静脈内(IV)および経口(PO)投与後の化合物に対する脳および血漿の曝露の評価
化合物1および2の特定の利点
方法:生存中
灌流および脳サンプリング方法
Ballistic染料標識および顕微鏡
ESP樹状突起スパイン解析および樹状膜の完全性の評価。
樹状サンプリング位置:
dHIPP、CA1アピカル2°(0〜50μm):
脳領域:背側海馬(dHIPP)
細胞型:CA1錐体ニューロン(CA1)
分枝の種類:アピカル
分岐次数:二次(2°)
サンプル位置:分岐点から0〜50μm
結果:
1)%ビヒクル=((棘密度またはSV2A点))/(平均ビヒクル棘密度またはSV2A点)x100
データを次いで、全棘密度の平均+/−SEM(ビヒクルからの増加%)として報告した。結果を表7に報告する。
発明の態様
[態様1]次式の化合物:
[態様2]態様1記載の化合物、またはその薬学的に許容される塩、および薬学的に許容される担体を含む組成物。
[態様3]対象においてHDAC活性を阻害する方法であって、有効量の態様1に記載の化合物もしくはその薬学的に許容される塩、または態様2に記載の組成物をそれを必要とする前記対象に投与する工程を含む、方法。
[態様4]神経学的障害、記憶もしくは認知機能障害または機能障害、学習消去障害、真菌性疾患もしくは感染、炎症性疾患、血液疾患、精神障害、および新生物性疾患から選択される対象における状態を治療する方法であって、有効量の態様1に記載の化合物、またはその薬学的に許容される塩、または態様2に記載の組成物をそれを必要とする前記対象に投与することを含む、方法。
[態様5]前記状態が、
a.アルツハイマー病、ハンチントン病、発作による記憶喪失、統合失調症、ルビンスタインテイビー症候群、レット症候群、うつ病、脆弱性X、レビー小体型認知症、血管性認知症、前頭側頭葉変性症(前頭側頭型認知症、FTD)、FTD−GRN、ADHD、失読症、双極性障害ならびに自閉症、外傷性頭部損傷、注意欠陥障害、不安障害、条件付き恐怖応答、パニック障害、強迫性障害、心的外傷後ストレス障害(PTSD)、恐怖症、社交不安障害、物質依存の回復、加齢関連性記憶障害(AAMI)、加齢関連性認知機能低下(ARCD)、運動失調症、パーキンソン病、もしくはパーキンソン病型認知症に関連する社会的障害、認知障害および学習障害に関連する認知機能障害または機能障害;または
b.急性骨髄性白血病、急性前骨髄球性白血病、急性リンパ芽球性白血病、慢性骨髄性白血病、骨髄異形成症候群、および鎌状赤血球貧血から選択される血液疾患;または
c.新生物性疾患;または
d.恐怖消去および心的外傷後ストレス障害から選択される学習消去障害
である、態様4に記載の方法。
[態様6]前記状態が、アルツハイマー病、ハンチントン病、前頭側頭型認知症、フリードライヒ失調症、心的外傷後ストレス障害(PTSD)、パーキンソン病、または物質依存の回復である、態様5に記載の方法。
Claims (8)
- 請求項1または2記載の化合物、またはその薬学的に許容される塩、および薬学的に許容される担体を含む組成物。
- 請求項1または2記載の化合物、またはその薬学的に許容される塩、および薬学的に許容される担体を含む、HDAC活性を阻害するための組成物。
- 請求項1または2記載の化合物、またはその薬学的に許容される塩、および薬学的に許容される担体を含む、神経学的障害、記憶もしくは認知機能障害または機能障害、学習消去障害、真菌性疾患もしくは感染、炎症性疾患、血液疾患、精神障害、および新生物性疾患から選択される状態を治療するための組成物。
- 前記状態が、
a.アルツハイマー病、ハンチントン病、発作による記憶喪失、統合失調症、ルビンスタインテイビー症候群、レット症候群、うつ病、脆弱性X、レビー小体型認知症、血管性認知症、前頭側頭葉変性症(前頭側頭型認知症、FTD)、FTD−GRN、ADHD、失読症、双極性障害ならびに自閉症、外傷性頭部損傷、注意欠陥障害、不安障害、条件付き恐怖応答、パニック障害、強迫性障害、心的外傷後ストレス障害(PTSD)、恐怖症、社交不安障害、物質依存の回復、加齢関連性記憶障害(AAMI)、加齢関連性認知機能低下(ARCD)、運動失調症、パーキンソン病、もしくはパーキンソン病型認知症に関連する社会的障害、認知障害および学習障害に関連する認知機能障害または機能障害;または
b.急性骨髄性白血病、急性前骨髄球性白血病、急性リンパ芽球性白血病、慢性骨髄性白血病、骨髄異形成症候群、および鎌状赤血球貧血から選択される血液疾患;または
c.新生物性疾患;または
d.恐怖消去および心的外傷後ストレス障害から選択される学習消去障害
である、請求項6に記載の組成物。 - 前記状態が、アルツハイマー病、ハンチントン病、前頭側頭型認知症、フリードライヒ失調症、心的外傷後ストレス障害(PTSD)、パーキンソン病、または物質依存の回復である、請求項7に記載の組成物。
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