JP6125505B2 - 小分子による電位開口型ナトリウムチャネル・アルファサブユニット関連疾患の治療 - Google Patents
小分子による電位開口型ナトリウムチャネル・アルファサブユニット関連疾患の治療 Download PDFInfo
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- JP6125505B2 JP6125505B2 JP2014528523A JP2014528523A JP6125505B2 JP 6125505 B2 JP6125505 B2 JP 6125505B2 JP 2014528523 A JP2014528523 A JP 2014528523A JP 2014528523 A JP2014528523 A JP 2014528523A JP 6125505 B2 JP6125505 B2 JP 6125505B2
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Description
配列番号1:ヒト電位開口性I型ナトリウムチャネル・アルファサブユニット(SCN1A)、転写変異体1、mRNA(NCBI寄託番号:NM_001165963)。
配列番号2:ヒト電位開口性II型ナトリウムチャネル・アルファサブユニット(SCN2A)、転写変異体1、mRNA(NCBI寄託番号:NM_021007.2)。
配列番号3:ヒト電位開口性III型ナトリウムチャネル・アルファサブユニット(SCN3A)、転写変異体1、mRNA(NCBI寄託番号:NM_006922.3)。
配列番号4:ヒト電位開口性IV型ナトリウムチャネル・アルファサブユニット(SCN4A)、mRNA(NCBI寄託番号:NM_000334.4)。
配列番号5:ヒト電位開口性V型ナトリウムチャネル・アルファサブユニット(SCN5A)、転写変異体1、mRNA(NCBI寄託番号:NM_198056.2)。
配列番号6:ヒト電位開口性VII型ナトリウムチャネル・アルファ(SCN7A)、mRNA(NCBI寄託番号:NM_002976.3)。
配列番号7:ヒト電位開口性VIII型ナトリウムチャネル・アルファサブユニット(SCN8A)、転写変異体1、mRNA(NCBI寄託番号:NM_014191.2)。
配列番号8:ヒト電位開口性IX型ナトリウムチャネル・アルファサブユニット(SCN9A)、mRNA(NCBI寄託番号:NM_002977.3)。
配列番号9:ヒト電位開口性X型ナトリウムチャネル・アルファサブユニット(SCN10A)、mRNA(NCBI寄託番号:NM_006514.2)。
配列番号10:ヒト電位開口性XI型ナトリウムチャネル・アルファサブユニット(SCN11A)、mRNA(NCBI寄託番号:NM_014139.2)。
配列番号11:ヒト電位開口型ナトリウムチャネル・アルファサブユニットSCN12A(SCN12A)、mRNA(NCBI寄託番号:AF109737.1)。 提供される配列表は、すべての場合において、実際は、RNS転写体のcDNAバージョンである。
本明細書で使用される用語の選択は、特定の実施形態を説明する目的でされたものであり、本発明を限定することを意図するものではない。本明細書で使用される場合、単数形の「a」、「an」、及び「the」は文脈において明らかに別記されない限り、複数形の内容も含むものとする。さらに、用語「含む」、「含める」、「有する」、「もつ」またはその変化形は、本明細書および/または添付の請求項において使用される場合、用語「包含する」と同様に非排他的な意味で用いられるものとする。
実施例
a)ミルナシプランHCl(1R(S),2S(R)[−2−(アミノメチル)−N,N−ジエチル−1−フェニルシクロプロパンカルボキサミドヒドロクロリド);
b)トルセミド(1−イソプロピル−3−[(4−m−トルイジノ−3−ピリジル−スルホニル]尿素);
c)リスペリドン(3−[2−[4−(6−フルオロ−1,2−ベンズイソキサゾール−3−イル)−1−ピペリジニル]−エチル]−6,7,8,9−テトラヒドロ−2−メチル−4H−ピリド[1,2−a]ピリミジン−4−オン);
d)ピナシジル(N−シアノ−N’ピリジン−4−イル−N’’−(1,2,2−トリメチルプロピル)グアニジン);
e)ベネジピンHCl(5−Oメチル−3O−[(3R)−1−(フェニルメチル)ピペリジン−3−イル]2,6−ジメチル−4−(3−ニトロフェニル)−1,4−ジヒドロピリジン−3,5−ジカルボキシレート);
f)ケトコナゾール(1−[4−(4−{[(2R,4S)−2−(2,4−ジクロロフェニル)−2−(1H−イミダゾール−1−イルメチル)−1,3−ジオキソラン−4−イル]メトキシ}フェニル)ピペラジン−1−イル]エタン−1−オン);
g)エブセレン(2−フェニル−1,2−ベンゾセレナゾール−3−オン);
h)タダラフィル((6R−トランス)−6−(1,3−ベンゾジオキソール−5−イル)−2,3,6,7,12,12a−ヘキサヒドロ−2−メチル−ピラジノ[1’,2’:1,6]ピリド[3,4−b]インドール−1,4−ジオン);
i)ゼラノール((3S,7R)−7,14,16−トリヒドロキシ−3−メチル−3,4,5,6,7,8,9,10,11,12−デカヒドロ−1H−2−ベンズオキサシクロテトラデシン−1−オン);
j)ネファザドンHCl(2−[3−[4−(3−クロロフェニル)−1−ピペラジニル]プロピル]−5−エチル−2,4−ジヒドロ−4−(2−フェノキシエチル)−3H−1,2,4−トリアゾール−3−オンモノヒドロクロリド;
k)ロメリジンジヒドロクロリド(1−[ビス(4−フルオロフェニル)メチル]−4−[2,3,4−トリメトキシフェニルメチル]ジヒドロクロリド);
l)イカリイン(5−ヒドロキシ−2−(4−メトキシフェニル)−8−(3−メチルブト−2−エニル)−7−[(2S,3R,4S,5S,6R)−3,4,5−トリヒドロキシ−6−(ヒドロキシメチル)オキサン−2−イル]オキシ−3−[(2S,3R,4R,5R,6S)−3,4,5−トリヒドロキシ−6−メチルオキサン−2−イル]オキシクロメン−4−オン);
m)オメプラゾールマグネシウム(6−メトキシ−2−((4−メトキシ−3,5−ジメチルピリジン−2−イル)メチルスルフィニル)−1H−ベンゾ[d]イミダゾールMg);
n)エソメプラゾールマグネシウム((S)−6−メトキシ−2−[(4−メトキシ−3,5−ジメチルピリジン−2−イル)メチルスルフィニル)−1H−ベンゾ[d]イミダゾールMg);
o)L−694,247(メタンスルホンアミド、N−[4−[[5−[3−(2−アミノエチル)−1H−インドール−5−イル]−1,2,4−オキサジアゾール−3−イル]メチル]フェニル];
p)ニトレンジピン((RS)−エチルメチル2,6−ジメチル−4−(3−ニトロフェニル)−1,4−ジヒドロピリジン−3,5−ジカルボキシレート);
q)ニメタゼパム(2−メチル−9−ニトロ−6−フェニル−2,5−ジアザビシクロ[5.4.0]ウンデカ−5,8,10,12−テトラエン−3−オン);
r)アンレキサノクス(2−アミノ−7−イソプロピル−5−オキソ−5H−クロメノ[2,3−b]ピリジン−3−カルボン酸);
s)モサプリドシトレート(4−アミノ−5−クロロ−2−エトキシ−N−[[4−[(4−フルオロフェニル)メチル]−2−モルホリニル]メチル]−ベンズアミド2−ヒドロキシ−1,2,3−プロパントリカルボキシレート);
t)セルトラリンヒドロクロリド((1S,4S)−4−(3,4−ジクロロフェニル)−N−メチル−1,2,3,4−テトラヒドロナフタレン−1−アミン)および
u)スタノゾロール(17β−ヒドロキシ−17−メチル−5α−アンドロスタノ[3,2−c]−ピラゾール)。
実施例1.小分子化合物での処置後にドラベ関連突然変異を保有する一次ヒト繊維芽細胞におけるSCN1A mRNAの上方調節
材料と方法
小分子化合物によるドラベ関連突然変異を保有する一次ヒト繊維芽細胞の処置
結果
実施例2.小分子化合物での処置後の成人一次ヒトケラチノサイトにおけるSCN1A mRNAの上方調節
材料と方法
小分子化合物による一次ヒトケラチノサイトの処置
結果
実施例4:酵素結合免疫吸着検定(ELISA)によるSCN1Aタンパク質の定量
実施例5:アクチンmRNAの定量
実施例6:免疫組織化学によるアクチンタンパク質の定量
実施例7:海馬錐体細胞においてSCN1A上方調節により誘導されるナトリウム電流振幅の変化
実施例8:海馬錐体細胞においてSCN1A上方調節により誘導されるナトリウム電流特性の変化
実施例9:細胞内ナトリウムレベルに及ぼすSCN1A上方調節の作用
実施例10:単一細胞中のナトリウムレベルに及ぼすSCN1A上方調節の影響
Claims (9)
- 生体系における電位開口性I型ナトリウムチャネル・アルファサブユニット(SCN1A)の発現を上方調節する方法において使用するための医薬組成物であって、
前記方法は、前記生体系を前記組成物と接触させることを含み、
前記組成物は、ミルナシプラン、トルセミド、リスペリドン、ピナシジル、ベニジピン、ケトコナゾール、エブセレン、タダラフィル、ゼラノール、ネファザドン、ロメリジン、イカリイン、オメプラゾール、エソメプラゾール、L−694,247、ニトレンジピン、ニメタゼパム、アンレキサノクス、モサプリド、セルトラリン、スタノゾロール、およびそれらの製薬上許容可能な塩、水和物、もしくは溶媒和物からなる群から選択される少なくとも1種の化合物を含む、
医薬組成物。 - in vivoまたはin vitroで患者の細胞または組織における電位開口性I型ナトリウムチャネル・アルファサブユニット(SCN1A)の発現を上方調節する方法において使用するための医薬組成物であって、
前記方法は、前記細胞または組織を前記組成物と接触させることを含み、
前記組成物は、ミルナシプラン、トルセミド、リスペリドン、ピナシジル、ベニジピン、ケトコナゾール、エブセレン、タダラフィル、ゼラノール、ネファザドン、ロメリジン、イカリイン、オメプラゾール、エソメプラゾール、L−694,247、ニトレンジピン、ニメタゼパム、アンレキサノクス、モサプリド、セルトラリン、スタノゾロール、およびそれらの製薬上許容可能な塩、水和物、もしくは溶媒和物からなる群から選択される少なくとも1種の化合物を含む、
医薬組成物。 - 前記発現が、in vivoで増大される、請求項1または2に記載の医薬組成物。
- 製薬上許容可能な賦形剤をさらに含む、請求項1〜3のいずれか1項に記載の医薬組成物。
- 電位開口性I型ナトリウムチャネル・アルファサブユニット(SCN1A)に関連した疾患の予防または治療に使用するための請求項1〜4のいずれか1項に記載の医薬組成物。
- 前記疾患が神経学的疾患または障害である、請求項5に記載の医薬組成物。
- 前記疾患が心臓血管性疾患または障害である、請求項5に記載の医薬組成物。
- 前記疾患が、痙攣、疼痛、慢性疼痛、ナトリウムチャネル機能不全を伴う電気的興奮性減損、ナトリウムチャネル機能不全に関連した疾患または障害、電位開口型ナトリウムチャネル・アルファサブユニット活性の誤調節に関連した疾患または障害、麻痺、高カリウム血性周期性四肢麻痺、先天性筋緊張症、カリウム増悪性筋緊張症、Q−T延長症候群3、運動終板疾患、運動失調、腸神経系の機能不全のための消化管疾患、結腸炎、回腸炎、炎症性腸症候群、高血圧症またはうっ血性心不全;交感神経および副交感神経性神経支配を伴う尿生殖器の疾患または障害、良性前立腺肥大、***不能症;神経筋系に関連した疾患または障害、筋ジストロフィー、多発性硬化症、癲癇、自閉症片頭痛、散発性および家族性片麻痺性片頭痛、乳児期の重症間代性筋痙攣(SMEIまたはドラベ症候群)、全身性癲癇熱性痙攣プラス(GEFS+)、およびSCN1A関連発作障害から選択される、請求項5に記載の医薬組成物。
- 前記疾患が、乳児期の重症間代性筋痙攣(SMEIまたはドラベ症候群)、家族性片麻痺性片頭痛、または全身性癲癇熱性痙攣プラス(GEFS+)から選択される、請求項5に記載の医薬組成物。
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- 2012-08-28 CN CN201280049885.3A patent/CN103874486A/zh active Pending
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CN103874486A (zh) | 2014-06-18 |
EA029151B1 (ru) | 2018-02-28 |
TW201317360A (zh) | 2013-05-01 |
US20140309181A1 (en) | 2014-10-16 |
WO2013036403A1 (en) | 2013-03-14 |
JP2014525446A (ja) | 2014-09-29 |
KR101991980B1 (ko) | 2019-06-21 |
CA2847811C (en) | 2019-10-22 |
CA2847811A1 (en) | 2013-03-14 |
EA201490420A1 (ru) | 2014-12-30 |
MX2014002668A (es) | 2014-06-04 |
TWI666325B (zh) | 2019-07-21 |
KR20140147800A (ko) | 2014-12-30 |
EP2753317A1 (en) | 2014-07-16 |
EP2753317A4 (en) | 2015-04-08 |
CL2014000550A1 (es) | 2014-09-22 |
MX365525B (es) | 2019-06-06 |
EP2753317B1 (en) | 2020-02-26 |
BR112014005234A2 (pt) | 2017-04-11 |
CN108272782B (zh) | 2021-04-23 |
US10583128B2 (en) | 2020-03-10 |
CN108272782A (zh) | 2018-07-13 |
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