JP2016540000A - 自閉症スペクトラム障害の治療のためのドーパミンd3受容体拮抗薬としてのクロモン誘導体 - Google Patents
自閉症スペクトラム障害の治療のためのドーパミンd3受容体拮抗薬としてのクロモン誘導体 Download PDFInfo
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Abstract
Description
A:数多くの状況にわたる社会的コミュニケーションおよび社会的相互作用(3項目全てが要求される)
・社会−感情的相互関係における欠陥
・社会的相互作用に用いられる非言語的な意思伝達の振る舞いにおける欠陥
・社会的関係性の構築および維持における欠陥
B:限られた繰り返される振る舞い(いずれか2項目が要求される)
・型にはまった、若しくは、繰り返される発言、身体の部位の動き、または物の使用
・日常的行動への過剰な執着、言語的または非言語的な振る舞いの儀式的様式、または変化への過剰な抵抗
・極めて(狭い範囲に)限定され執着された、その対象への集中強度が異常な興味関心
・感覚器を通しての入力に対する過反応性若しくは反応性低下、または周囲の状況についての感覚的様相への普通ではない興味関心
C:症状は発達初期に顕在化しなければならない。
D:症状は、臨床上顕著な社会的、職業的、または他の重要な最新の機能における障害を引き起こす。
E:これらの障害は、知的障害、または包括的な発育遅延では、よりよく説明できない。
・社会的行動の障害
・型にはまった、若しくは、繰り返される行動様式
・感覚およびコミュニケーションの障害
加えて、その表現型は、前頭前皮質における神経細胞の樹状突起の数または密度の減少等の、ASD特有の形態的再構成も含まれる(Bringas et al., Neuroscience 2013, vol 241, p 170-187)。これは、バルプロエートラットモデルに、ASDの病態生理学的動物モデルとしての構成概念妥当性および表面的妥当性を付与する。
N−(3−{4−[4−(8−オキソ−8H−[1,3]ジオキソロ[4,5−g]クロメン−7−イル)−ブチル]−ピペラジン−1−イル}−フェニル)−メタンスルフォンアミド塩酸塩は、ヒト組換えドーパミンD3受容体発現細胞またはヒト組換えドーパミンD2受容体発現細胞における、本発明に従ったそのレセプターに対するドーパミンD3受容体リガンドおよびモジュレーターとしてのインビトロの活性により評価された。阻害定数(Ki)は、キューサックらの文献(Cussac et al., in Naunyn-Schmiedeberg's Arch. Pharmacol. 2000, vol 361, p 569-572)に記載された、[3H]スピペロンの結合の阻害により測定された。発明者らは、本発明化合物が、Ki値が0.17〜ナノモル/Lである、強力なドーパミンD3受容体リガンドとして作用することを示した。この化合物は、ドーパミンD2受容体リガンドに対しては、検出可能な親和性(71倍弱い)を示した。
N−(3−{4−[4−(8−オキソ−8H−[1,3]ジオキソロ[4,5−g]クロメン−7−イル)−ブチル]−ピペラジン−1−イル}−フェニル)−メタンスルフォンアミド塩酸塩は、バルプロ酸ナトリウム塩を投与された雌ラットからの出生児の社会的相互作用に関して試験された。自閉症についてのバルプロ酸ラットモデルの実験の設定は、発表されているデータ(Dendrinos et al., Front. Integr. Neurosci. 2011, vol 5, art 68; Markram et al., Neuropsychopharm. 2007, vol 33, p 901-912; Schneider et al., Neuropsychopharm. 2005, vol 30, p 80-89)に適合させた。
妊娠している(最大胎生期8日)雌スプラーグドーリーラット(OFA (SD) Charles River Lyon, France)は、4日間隔離された。動物は、環境的に調節された部屋(温度21±1℃、相対湿度55±5%)中、12時間おきの明暗サイクル(午前7時にライトは点灯する)の下で、食餌(A04, Safe, Augy, France)および濾過水(孔直径は0.2μm)を自由に摂取できる、フルボトムケージ(ML-H Cage, 370x235x180 mm, LxWxH; floor surface 870 cm2)に、ケージ毎に2匹ずつ収容された。出生児を離乳させるまでは、動物は、できる限り邪魔しないように、1週間に1回だけしか変えなかった。環境的富化(営巣材料)を提供した。
生理食塩水またはバルプロエートナトリウムのいずれかで処理された母親からの出生児の社会的相互作用の振る舞いに関する本発明化合物の急性投与の効果は、図1に概略が示される。示されたデータは、平均値±平均値に対する標準誤差、n=10匹のラット(5匹の雄ラットおよび5匹の雌ラット)である。本発明化合物は、生理食塩水で処理された母親からの出生児における社会的相互作用の振る舞いには顕著な効果をもたらさなかった。本発明化合物を0.63mg/kg投与した場合に、出生前のバルプロエートナトリウムへの曝露により引き起こされた社会的相互作用の欠陥を顕著に軽減した。本発明化合物を2.5mg/kg投与した場合に、これらの欠陥は完全に逆転させられた。本発明化合物は、自閉症スペクトラム障害および特に社会的相互作用の欠陥の治療のための興味深い製品であると考えられる。
Claims (6)
- 自閉症スペクトラム障害の治療のための薬剤として使用するための、N−(3−{4−[4−(8−オキソ−8H−[1,3]ジオキソロ[4,5−g]クロメン−7−イル)−ブチル]−ピペラジン−1−イル}−フェニル)−メタンスルフォンアミドまたはその薬学的に許容可能な塩。
- 薬学的に許容可能な塩が塩酸塩である、請求項1に記載の使用のためのN−(3−{4−[4−(8−オキソ−8H−[1,3]ジオキソロ[4,5−g]クロメン−7−イル)−ブチル]−ピペラジン−1−イル}−フェニル)−メタンスルフォンアミド。
- 社会的相互作用の欠陥の治療のための薬剤として使用するための、請求項1または2に記載の使用のためのN−(3−{4−[4−(8−オキソ−8H−[1,3]ジオキソロ[4,5−g]クロメン−7−イル)−ブチル]−ピペラジン−1−イル}−フェニル)−メタンスルフォンアミド。
- N−(3−{4−[4−(8−オキソ−8H−[1,3]ジオキソロ[4,5−g]クロメン−7−イル)−ブチル]−ピペラジン−1−イル}−フェニル)−メタンスルフォンアミドまたはその薬学的に許容可能な塩と薬学的に許容可能な賦形剤とを含んでなる、自閉症スペクトラム障害の治療のための医薬組成物。
- 社会的相互作用の欠陥の治療のための、請求項4に記載の使用のための医薬組成物。
- メマンチン、アマンタジン、バクロフェン、R−バクロフェン、フェノバム(phenobam)、アカンプロセート、ブメタミド(bumetamide)、カルピプラミン、オキシトシン、バソプレシンおよびこれらの混合物、からなる群から選択される化合物と組合せられた、請求項4または5に記載の使用のための医薬組成物。
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