JP2022116307A - 障害を治療するための5ht作動薬 - Google Patents
障害を治療するための5ht作動薬 Download PDFInfo
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- JP2022116307A JP2022116307A JP2022091363A JP2022091363A JP2022116307A JP 2022116307 A JP2022116307 A JP 2022116307A JP 2022091363 A JP2022091363 A JP 2022091363A JP 2022091363 A JP2022091363 A JP 2022091363A JP 2022116307 A JP2022116307 A JP 2022116307A
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- JP
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- Prior art keywords
- receptor agonist
- receptor
- pharmaceutically acceptable
- epilepsy
- clemizole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
本願は癲癇症の治療方法を提供する。1態様において、前記方法は前記治療を必要とする対象に治療有効量の5-HT受容体作動薬又はその医薬的に許容される塩を投与することによる癲癇症の治療方法である。別の態様において、前記方法は前記治療を必要とする対象に本願に記載するような医薬組成物を投与することによる癲癇症の治療方法であり、前記医薬組成物は5-HT受容体作動薬又はその医薬的に許容される塩を含有する。対象はケト原性食を摂取しているものとすることができる(例えばケト原性食に従う食物を摂取しているものとすることができる)。対象は心血管疾患をもつものとすることができる。対象はセロトニン再取り込み阻害薬による治療に耐性のものとすることができる。対象はセロトニン再取り込み阻害薬を投与した場合の副作用に感受性のものとすることができる。対象は小児(例えば小児癲癇病態をもつ対象)とすることができる。
本願は上記疾患及び障害を治療するのに有用な5-HT受容体作動薬又はその医薬的に許容される塩を含有する医薬組成物を提供する。前記医薬組成物は本願に記載するように錠剤、散剤、カプセル剤、丸剤、カシェ剤又はロゼンジ剤として製剤化することができる。前記医薬組成物は経口投与用に錠剤、カプセル剤、丸剤、カシェ剤又はロゼンジ剤として製剤化することができる。前記医薬組成物は例えば静脈内投与等の技術により投与するために溶液に溶解させるように製剤化することができる。前記医薬組成物は本願に記載するように経口投与、坐剤投与、局所投与、静脈内投与、腹腔内投与、筋肉内投与、病変内投与、髄腔内投与、鼻腔内投与、皮下投与、移植、経皮投与又は経粘膜投与用に製剤化することができる。
本願に記載する5-HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は多様な経口、非経口及び局所剤形で製造及び投与することができる。従って、本願に記載する5-HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は注射により(例えば静脈内、筋肉内、皮内、皮下、十二指腸内又は腹腔内に)投与することができる。また、本願に記載する5-HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は吸入により例えば鼻腔内に投与することもできる。更に、前記5-HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は経皮投与することもできる。前記5-HT受容体作動薬(その医薬的に許容される塩を含む)又はこれを含有する医薬組成物を投与するために複数の投与経路(例えば筋肉内、経口、経皮)を使用できるとも予想される。本願に記載する医薬組成物は医薬的に許容される担体又は賦形剤と、5-HT受容体作動薬(その医薬的に許容される塩を含む)の1種以上を含有することができる。本願に記載する医薬組成物は医薬的に許容される担体又は賦形剤と、5-HT受容体作動薬(その医薬的に許容される塩を含む)の1種以上と、本願に記載するような1種以上のAEDを含有することができる。
前記医薬組成物は治療有効量、即ちその所期目的を達成するために有効な量の前記5-HT受容体作動薬(その医薬的に許容される塩を含む)を含有することができる。特定の用途に有効な実際の量は特に治療する病態により異なる。例えば、癲癇症(例えばドラベ症候群)の治療方法で投与する場合、このような組成物は所望の結果(例えば発作の抑制)を達成するために有効な量の前記5-HT受容体作動薬(その医薬的に許容される塩を含む)又はその医薬組成物を含有する。
特定の化合物の毒性と治療効果の比はその治療指数であり、LD50(集団の50%が死亡する化合物の量)とED50(集団の50%で有効な化合物の量)の比として表すことができる。治療指数の高い化合物が好ましい。人体用投与量範囲を処方するには、細胞培養アッセイ及び/又は動物試験から得られた治療指数データを使用することができる。このような化合物の投与量は毒性を殆ど又は全く生じることなしにED50を含む血漿濃度の範囲内にあることが好ましい。用量は利用する剤形と利用する投与経路に応じてこの範囲内で変えることができる。例えばFingl et al.,In:THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,Ch.1,p.l,1975参照。厳密な処方、投与経路及び投与量は患者の病態と化合物を使用する特定の方法に鑑みて個々の医師が選択することができる。
癲癇は脳の損傷又は遺伝子突然変異の結果として生ずる。遺伝的癲癇としては、SCN1A遺伝子で650種類を超える変異体が同定されている(Harkin,L.A.et al.The spectrum of SCN1A-related infantile epileptic encephalopathies.Brain 130,843-852(2007);Mulley J.C.,et al.,SCN1A mutations and epilepsy.Hum.Mutat.25,535-542(2005))。この遺伝子のミスセンス又はフレームシフト突然変異は全般癲癇熱性痙攣プラス(GEFS+)(Ceulemans,B.P.,et al.,Clinical correlations of mutations in the SCN1A gene:from febrile seizures to severe myoclonic epilepsy in infancy.Pediatric Neurol.30,236-243(2004))と、ドラベ症候群と呼ばれるより重度の障害に関連している。DSの小児は最初に正常な発育を示すが、生後1年以内に熱性痙攣エピソードを生じることが多く、その結果、重度の自発性反復性発作、知的障害、運動失調及び精神運動機能障害に進行する。発作は入手可能な抗癲癇薬(AED)を使用して十分に管理されず、これらの小児は脳神経外科的切除の候補としては不適切である(Bender,A.C.,et al.,SCN1A mutations in Dravet syndrome:Impact of interneuron dysfunction on neural networks and cognitive outcome.Epilepsy Beh.23,177-186(2012))。
本発明者らのこれまでの検討と、マウスの定性的MESスクリーニングで100mg/kgと300mg/kgの用量で認められた若干の活性に基づき、MES/scMET/Toxマウスモデルで定量的試験を進め、ED50/TD50を求めた。MESモデルでTPEを求める間に、300mg/kgの出発時の用量で活性は認められなかった。一方、500mg/kgの用量では活性が認められ、4匹のうちの2匹が0.25分、4匹のうちの4匹が30分で保護された。試験した他のどの用量又は試験時点でも活性又は毒性(回転棒を掴めない)は認められなかった。scMETモデルでは活性が認められなかった。MESモデルのデータによると、このマウスモデルではASP469016により有意な活性/保護が得られ、ED50<400mg/kgである。
本発明者らの初期T31(MES/scMET/Tox)スクリーニングではASP469016を30mg/kg、100mg/kg及び300mg/kgで試験した。各条件のデータをN/Fとして表し、ここでNは保護された動物数であり、Fは試験した動物数である。毒性(TOX)試験では、Nは毒性作用を示す動物数であり、Fは試験した動物数である。C列のコードは実験を実施する技術者からのコメントを意味し、必要に応じてコメントセクションに定義する。死亡は認められない。6Hz(32mA)モデルに示すように、100mg/kgで30分にて4匹中の1匹のみが保護された。MESにより誘発させた発作モデルでは、100mg/kgと300mg/kgで30分にて4匹中の1匹のみが保護された。試験した他のどの用量又は時点でも毒性(回転棒を掴めない)又は活性は検出されなかった。
139種類の異なるインビトロ受容体結合アッセイ及び酵素アッセイの集合であるCEREP BioPrint Profileでクレミゾール(149934-L6)を試験した。初期BioPrintスクリーニングには、10μΜ(1.0E-5M)の遊離化合物濃度を使用した。各標的に特異的な放射性標識リガンドの結合の阻害率%として化合物結合性を計算した。対照酵素活性の阻害率%として化合物酵素阻害効果を計算した。各実験で夫々の基準化合物をクレミゾール(149934-L6)と同時に試験し、CEREPで測定された歴史的数値とデータを比較した。実験はCEREPの検証標準操作手順に従って承認された。50%よりも高い阻害(又は基礎条件で実施したアッセイの刺激)を示す結果が試験化合物の有意な効果に相当するとみなされる。これらの結果をまとめたものを以下に示す。
クレミゾールは抗ヒスタミン薬の作用機序により抗癲癇活性を発揮するものではない。32種類の異なる抗ヒスタミン化合物(図10)をscn1Labゼブラフィッシュアッセイでスクリーニングした処、クレミゾールの抗癲癇作用と似ている化合物は皆無であった。化合物のうちの3種類は毒性であり、抗ヒスタミン薬が小児癲癇患者における発作を悪化させるという臨床報告通りに、5種類の化合物は発作行動を亢進させた。
出願人らはセロトニンシグナル伝達経路に作用する62種類の薬物を含むSelleck Customized Libraryをスクリーニングした。これらの化合物を先ずゼブラフィッシュ移動運動アッセイでスクリーニングした処、図11に示すように、15種類の化合物が初回通過移動運動アッセイ(アッセイの詳細についてはBaraban et al.Nat.Comm.2013及びDinday and Baraban,eNeuro 2015を参酌できる)で陽性ヒットと認定された。これらの試験は、5HTシグナル伝達の調節、特にシナプス後部5HT受容体の活性化が潜在的な抗癲癇効果をもつことを示唆している。
実施形態1.癲癇症の治療方法であって、前記治療を必要とする対象に治療有効量の5HT受容体作動薬又はその医薬的に許容される塩を投与することを含む前記方法。
Claims (58)
- 癲癇症の治療方法であって、前記治療を必要とする対象に治療有効量の5HT受容体作動薬又はその医薬的に許容される塩を投与することを含む前記方法。
- 前記5HT受容体作動薬が、5HT2A受容体作動薬又は5HT2B受容体作動薬である請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT2A受容体と5HT2B受容体の両方の作動薬である請求項2に記載の方法。
- 前記5HT受容体作動薬が、クレミゾール又はフェンフルラミン以外のものである請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体と直接結合する請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体を特異的に活性化させる請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT2C受容体により介在される活性を同等以下にしながら5HT2A受容体又は5HT2B受容体により介在される活性を増加させる請求項1に記載の方法。
- 前記5HT受容体作動薬が、セロトニン再取り込み阻害薬以外のものである請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT1A、5HT1B、5HT1D、5HT2C、5HT3、5HT4、5HT6、5HT7、NPY Y1受容体、L型Caチャネル、N型Caチャネル、SK-Caチャネル、GABA依存性Clチャネル、GABAトランスポーター、GABA-A1受容体、GABA-B1b受容体、Naチャネル、5HTトランスポーター、CB1受容体、CB2受容体、BZD又はエストロゲンERαの少なくとも1種と有意に結合しないか又はその活性を調節しない請求項1に記載の方法。
- 前記5HT受容体作動薬が、フリバンセリン、DOI HCl、ノルフェンフルラミン又はBW723C86である請求項1に記載の方法。
- 前記5HT受容体作動薬が、スマトリプタン、ナラトリプタン、リザトリプタン、ゾルミトリプタン、ウラピジル、BRL-54443(3-(1-メチルピペリジン-4-イル)-1H-インドール-5-オール)、ロルカセリン、ブスピロン、ジプラシドン、TCB-2((4-ブロモ-3,6-ジメトキシベンゾシクロブテン-1-イル)メチルアミン臭化水素酸塩)、BRL-15572(3-(4-(4-クロロフェニル)ピペラジン-1-イル)-1,1-ジフェニル-2-プロパノール)、トラゾドン、BMY7378(8-(2-[4-(2-メトキシフェニル)-1-ピペラジニル]エチル)-8-アザスピロ[4.5]デカン-7,9-ジオン)、アトモキセチン又はベンラファキシンである請求項1に記載の方法。
- 前記5HT受容体作動薬が、トラゾドンである請求項1に記載の方法。
- 前記癲癇症が、ドラベ症候群、レノックス・ガストー症候群、点頭癲癇又は大田原症候群である請求項1に記載の方法。
- 前記癲癇症が、ドラベ症候群である請求項13に記載の方法。
- 前記癲癇症が、小児癲癇症である請求項1に記載の方法。
- 前記対象が、心血管疾患をもつ請求項1に記載の方法。
- 前記対象が、セロトニン再取り込み阻害薬による治療に耐性である請求項1に記載の方法。
- 前記対象が、セロトニン再取り込み阻害薬を投与した場合の副作用に感受性である請求項1に記載の方法。
- 前記セロトニン再取り込み阻害薬が、フェンフルラミンである請求項17又は18に記載の方法。
- 前記対象が、ケト原性食を摂取している請求項1に記載の方法。
- 前記5HT受容体作動薬が、癲癇対象、アルツハイマー病対象、自閉症対象又はパーキンソン病対象における強迫行為又はエレクトログラフ発作を抑制する請求項1に記載の方法。
- 前記5HT受容体作動薬が、前記5HT受容体作動薬の不在下と比較した場合に前記対象における非誘発性発作の発生を抑制する請求項1に記載の方法。
- 前記5HT受容体作動薬の前記投与が、5HT受容体作動薬の不在下と比較した場合に前記対象におけるミオクローヌス発作又は癲癇重積状態を抑制又は予防する請求項1に記載の方法。
- 前記5HT受容体作動薬を体重1kg当たり約0.1mg~約1000mgの量で前記対象に投与する請求項1に記載の方法。
- 前記5HT受容体作動薬を体重1kg当たり約0.1mg~約1000mgの1日用量で前記対象に投与する請求項22に記載の方法。
- 前記5HT受容体作動薬を抗癲癇薬(AED)と併用投与する請求項1に記載の方法。
- 前記5HT受容体作動薬が、抗癲癇薬(AED)の補助療法である請求項1に記載の方法。
- 前記AEDが、アセタゾラミド、ベンゾジアゼピン、カンナビジオール、カルバマゼピン、クロバザム、クロナゼパム、エスリカルバゼピン酢酸塩、エトスクシミド、エトトイン、フェルバメート、フェンフルラミン、フォスフェニトイン、ガバペンチン、ガナキソロン、フペルジンA、ラコサミド、ラモトリギン、レベチラセタム、ニトラゼパム、オクスカルバゼピン、ペランパネル、ピラセタム、フェノバルビタール、フェニトイン、臭化カリウム、プレガバリン、プリミドン、レチガビン、ルフィナミド、バルプロ酸、バルプロ酸ナトリウム、スチリペントール、チアガビン、トピラマート、ビガバトリン又はゾニサミドである請求項26又は27に記載の方法。
- 前記AEDが、バルプロ酸、バルプロ酸ナトリウム、クロナゼパム、エトスクシミド、フェルバメート、ガバペンチン、カルバマゼピン、オクスカルバゼピン、ラモトリギン、レベチラセタム、ベンゾジアゼピン、フェノバルビタール、プレガバリン、プリミドン、チアガビン、トピラマート、臭化カリウム、フェニトイン、スチリペントール、ビガバトリン又はゾニサミドである請求項28に記載の方法。
- 前記AEDが、バルプロ酸、バルプロ酸ナトリウム、ガバペンチン、トピラマート、カルバマゼピン、オクスカルバゼピン又はビガバトリンである請求項29に記載の方法。
- 前記AEDが、フェンフルラミン又はトピラマート以外のものである請求項26に記載の方法。
- 前記AEDを前記5HT受容体作動薬と同時又は順次投与する請求項26に記載の方法。
- 癲癇症の治療方法であって、前記方法が前記治療を必要とする対象に治療有効量の5HT受容体作動薬又はその医薬的に許容される塩を投与することを含み、前記対象が心血管疾患をもつか、セロトニン再取り込み阻害薬による治療に耐性であるか、又はセロトニン再取り込み阻害薬を投与した場合の副作用に感受性である前記方法。
- 前記5HT受容体作動薬が、5HT2A受容体作動薬又は5HT2B受容体作動薬である請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT2A受容体と5HT2B受容体の両方の作動薬である請求項32に記載の方法。
- 前記5HT受容体作動薬が、クレミゾール、クレミゾールアナログ又はその医薬的に許容される塩である請求項33に記載の方法。
- 前記医薬的に許容される塩がクレミゾールHClである請求項36に記載の方法。
- 前記クレミゾール、前記クレミゾールアナログ又は前記その医薬的に許容される塩が医薬組成物の一部を形成する請求項36に記載の方法。
- 前記医薬組成物が更に医薬的に許容される賦形剤を含有する請求項38に記載の方法。
- 前記医薬組成物が、治療有効量のクレミゾール、前記クレミゾールアナログ又は前記その医薬的に許容される塩を含有する請求項38に記載の方法。
- 前記医薬組成物を抗癲癇薬(AED)と併用投与する請求項40に記載の方法。
- 前記医薬組成物が、クレミゾール、前記クレミゾールアナログ又は前記その医薬的に許容される塩と、AEDを含有する請求項41に記載の方法。
- 前記5HT受容体作動薬が、フェンフルラミン以外のものである請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体と直接結合する請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体を特異的に活性化させる請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT2C受容体により介在される活性を同等以下にしながら5HT2A受容体又は5HT2B受容体により介在される活性を増加させる請求項33に記載の方法。
- 前記5HT受容体作動薬が、セロトニン再取り込み阻害薬以外のものである請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT1A、5HT1B、5HT1D、5HT2C、5HT3、5HT4、5HT6、5HT7、NPY Y1受容体、L型Caチャネル、N型Caチャネル、SK-Caチャネル、GABA依存性Clチャネル、GABAトランスポーター、GABA-A1受容体、GABA-B1b受容体、Naチャネル、5HTトランスポーター、CB1受容体、CB2受容体、BZD又はエストロゲンERαの少なくとも1種と有意に結合しないか又はその活性を調節しない請求項33に記載の方法。
- 前記5HT受容体作動薬が、スマトリプタン、ナラトリプタン、リザトリプタン、ゾルミトリプタン、ウラピジル、BRL-54443(3-(1-メチルピペリジン-4-イル)-1H-インドール-5-オール)、ロルカセリン、ブスピロン、ジプラシドン、TCB-2((4-ブロモ-3,6-ジメトキシベンゾシクロブテン-1-イル)メチルアミン臭化水素酸塩)、BRL-15572(3-(4-(4-クロロフェニル)ピペラジン-1-イル)-1,1-ジフェニル-2-プロパノール)、トラゾドン、BMY7378(8-(2-[4-(2-メトキシフェニル)-1-ピペラジニル]エチル)-8-アザスピロ[4.5]デカン-7,9-ジオン)、アトモキセチン又はベンラファキシンである請求項33に記載の方法。
- 前記5HT受容体作動薬が、トラゾドン又はその医薬的に許容される塩である請求項33に記載の方法。
- 5HT受容体をクレミゾール、クレミゾールアナログ又はその医薬的に許容される塩と接触させることを含む5HT受容体の活性の調節方法。
- 前記調節が、活性化である請求項51に記載の方法。
- 前記5HT受容体が、5HT2A受容体又は5HT2B受容体である請求項51に記載の方法。
- 脳内のセロトニンの不足により又は1種以上の5HT受容体の活動下で生じる疾患又は障害の治療方法であって、前記治療を必要とする対象に治療有効量のクレミゾール、クレミゾールアナログ又はその医薬的に許容される塩を投与することを含む前記方法。
- 前記疾患又は障害が、癲癇以外のものである請求項54に記載の方法。
- 前記疾患又は障害が、ドラベ症候群以外のものである請求項54に記載の方法。
- 前記疾患又は障害が、片頭痛、脆弱X症候群、プラダー・ウィリー症候群、統合失調症、鬱病、アルツハイマー病、自閉症、神経障害性疼痛、パーキンソン病、過敏性腸症及び認知症から構成される群から選択される請求項51に記載の方法。
- 前記医薬的に許容される塩が、クレミゾールHClである請求項50に記載の方法。
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