JP6768662B2 - Nadphオキシダーゼに関連する状態の処置に使用するための化合物 - Google Patents
Nadphオキシダーゼに関連する状態の処置に使用するための化合物 Download PDFInfo
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Description
酵素Noxファミリーが産生する反応性酸素種は、スーパーオキシドO2 −または過酸化水素H2O2のいずれかである。
Nox4もp22phoxと会合し、この形態で構成性活性である。しかし、Nox4活性はアセンブリーまたはリガンド活性化によってではなく発現によって調節され、これによりこのイソ型は他のイソ型と区別される(Serrander et al., Biochem J. 406, 2007)。Nox4は、誘導されると一般にNox1および2より高いレベルで発現する(Ago et al., Circulation, 109, 2004)。Nox4は、他のNoxバリアントのようなO2 −ではなく主にH2O2を発生すると思われる(Takac et al., J. Biol. Chem. 286, 2011)。これがこのイソ型をユニークなものにしている;H2O2は、膜を通過する能力、したがってきわめて短い半減期をもつO2 −より遠く離れた場所で作用する能力をもつからである。
Nox4と疾患 − 他のイソ型と比較したNox4の独自性は、療法ターゲットとしての独自性とも関係がある;それは過剰発現すると多種多様な疾患に関与すると思われるからである。
siRNA仲介によるNox4ノックダウンはNADPHオキシダーゼ活性を有意に低下させることが、メサンギウム細胞および腎皮質から精製したミトコンドリアにおいて立証された。このノックダウンは、グルコース誘導によるミトコンドリアのスーパーオキシド産生をブロックした。Nox4は糖尿病においてミトコンドリア機能異常および細胞傷害をもたらす可能性がある酸化的ストレスに対する中心的なメディエーターとして作用することが示唆された(Block et al., PNAS vol. 106, no. 34, 2009)。
Nox4は不全性心臓の病理に強く関係づけられてきた(Nabeebaccus A et al. “NADPH oxidases and cardiac remodeling” Heart Fai Rev. 2011; Kuroda J et al., “NADPH oxidase and cardiac failure Cardiovasc Transl Res. 2010; Kuroda J et al., “NADPH oxidase 4 is a major source of oxidative stress in the failing heart” Proc Natl Acad Sci USA 2010)。ミトコンドリアNox4活性の増大と“老化性心臓”の機能障害との関係が示唆された(Tetsuro Ago et al., AGING, December 2010, vol.2 No 12)。
pは、0から2までの整数であり;
qは、0から2までの整数であり;
mは、1から3までの整数であり;
nは、0から3までの整数であり;
R1はそれぞれ、独立してC1−C3アルキル−X−から選択され;
Xはそれぞれ、独立して直接結合、O、およびSから選択され;
R2はそれぞれ、独立してC1−C3アルキル−Y−、およびフェニル−(CH2)z−Y−から選択され;
Yはそれぞれ、独立してOおよびSから選択され;
zはそれぞれ、独立して0および1から選択される]
またはその医薬的に許容できる塩であって、
内分泌障害、心血管障害、呼吸器障害、代謝障害、皮膚障害、骨障害、神経炎症性障害、腎疾患、生殖障害、眼および/または水晶体を冒す疾患、ならびに/あるいは内耳を冒す状態、炎症性障害、肝疾患、痛み、癌、アレルギー性障害、外傷性障害、敗血症性、出血性およびアナフィラキシー性のショック、胃腸系の疾患または障害、異常な血管新生および血管新生依存性状態から選択される、ニコチンアミドアデニンジヌクレオチドリン酸オキシダーゼ活性に関連する状態または障害の処置に使用するための化合物が提供される。
用語“外傷性障害(traumatism)”は、多発性外傷性障害(polytraumatism)を含む。
用語“代謝に影響を及ぼす疾患または障害”は、肥満症、メタボリックシンドロームおよびII型糖尿病を含む。
用語“骨障害”は、骨粗鬆症、オステオポラシス(osteoporasis)、骨硬化症、歯周炎、および副甲状腺機能亢進症を含む。
用語“眼および/または水晶体を冒す疾患または障害”は、糖尿病性白内障を含めた白内障、白内障手術後の水晶体の再混濁化、糖尿病性その他の形態の網膜障害を含む。
用語“関節炎”は、下記のものを意味する:急性関節リウマチ、慢性関節リウマチ、クラミジア関節炎、慢性吸収性関節炎(chronic absorptive arthritis)、乳糜(び)関節炎(anchylous arthritis)、腸疾患に起因する関節炎、フィラリア性関節炎、淋菌性関節炎、痛風性関節炎、血友病性関節炎、肥厚性関節炎、若年性慢性関節炎、ライム関節炎、新生子ウマ関節炎(neonatal foal arthritis)、結節性関節炎、アルカプトン尿性関節炎、乾癬性関節炎または化膿性関節炎、あるいはNADPHオキシダーゼを阻害するのに十分な用量で療法有効量の式(I)により表わされる化合物を哺乳動物に投与する必要がある関連疾患。
用語“癌”は、下記のものを意味する:癌腫(たとえば、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮腫、骨膜腫、中皮腫、ユーイング腫、平滑筋肉腫、横紋筋肉腫、大腸癌、膵臓癌、乳癌、卵巣癌、腎癌、前立腺癌、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、脂腺癌、乳頭状癌、乳頭状腺癌、嚢胞腺癌、髄様癌、気管支原性癌、腎細胞癌、肝細胞癌、胆管癌、絨毛癌、精上皮腫、胎児性癌、ウィルムス腫瘍、子宮頚癌、精巣腫瘍、肺癌、小細胞肺癌、肺腺癌、膀胱癌、または上皮癌)、またはNADPHオキシダーゼを阻害するのに十分な用量で療法有効量の式(I)により表わされる化合物を哺乳動物に投与する必要がある関連疾患。
用語“血管新生(angiogenesis)”は、発芽血管新生(sprouting angiogenesis)、嵌入血管新生(intussusceptive angiogenesis)、血管形成(vasculogenesis)、動脈形成、およびリンパ管形成を含む。血管新生は、既存の毛細管または後毛細管細静脈からの新たな血管の形成であり、癌、関節炎および炎症などの病的状態で起きる。血管新生刺激に際して血管が侵入できる皮膚、筋肉、腸、結合組織、関節、骨などの組織を含めた多種多様な組織または組織化された組織からなる臓器が、疾患状態における血管新生を支持することができる。本明細書中で用いる用語“血管新生依存性状態”は、血管新生または血管形成のプロセスが病的状態を持続または補足する状態を意味するものとする。血管形成は、内皮細胞前駆体である血管芽細胞から生じる新たな血管の形成の結果である。両プロセスとも結果的に新たな血管を形成し、血管新生依存性状態という用語の意味に含まれる。同様に、本明細書中で用いる用語“血管新生”は、デノボ血管形成、たとえば血管形成から生じるもの、ならびに既存の血管、毛細管および細静脈の分枝および発芽から生じるものを含むものとする。
用語Cn−Cm(mおよびnは両方とも整数であり、m>nである)は、少なくともn個、最大でm個の炭素原子を含む基または部分を表わす。したがって、用語C1−C6アルキルは、1、2、3、4、5または6個の炭素原子を含むことができるアルキル基を表わす。
式(I)の化合物において、mは1、2または3である。ある態様において、mは1である。ある他の態様において、mは2である。さらに他の態様において、mは3である。ある他の態様において、mは1または3である。さらに他の態様において、mは2または3である。
Xはそれぞれ、独立して直接結合、OおよびSから選択される。ある態様において、Xはそれぞれ直接結合およびOから選択される。ある態様において、Xはそれぞれ直接結合である。ある態様において、XはそれぞれOまたはSであり、たとえばXはそれぞれOである。
部分フェニル−(CH2)z−Y−において、zは0および1から選択される整数である。ある態様において、zは0である。ある他の態様において、zは1である。
ある態様において、式(I)の化合物は式(Ia)
ある特定の態様において、式(I)の化合物は式(Ie)
ある態様において、式(I)の化合物は下記のものから選択される:
式(I)の化合物は市販されているか、あるいは当技術分野で周知の方法により、容易に入手できる出発物質から一般的な方法および手順を用いて製造できる。
通常は、有効化合物の有効量は製剤の0.1〜95重量%、好ましくは非経口用製剤中には0.2〜20重量%、好ましくは経口投与用製剤中には1〜50重量%である。
(A)本明細書中で定める本発明化合物;および
(B)他の療法剤;
その際、(A)および(B)を医薬的に許容できる賦形剤との混合物中に配合する。
(1)本発明に従って使用するための前記に定めた化合物、他の療法剤、および医薬的に許容できる賦形剤、たとえば佐剤、希釈剤またはキャリヤーを含有する、医薬配合物;ならびに
(2)構成要素として下記のものを含むパーツのキット:
(a)本発明に従って使用するための本明細書中で定めた化合物を、医薬的に許容できる賦形剤、たとえば佐剤、希釈剤またはキャリヤーと混合したものを含有する、医薬配合物;および
(b)他の療法剤を、医薬的に許容できる賦形剤、たとえば佐剤、希釈剤またはキャリヤーと混合したものを含有する、医薬配合物;
それらの構成要素(a)および(b)はそれぞれ、他方と組み合わせて投与するのに適した形態で提供される。
1観点によれば、ニコチンアミドアデニンジヌクレオチドリン酸オキシダーゼ(Nox)、特にNox4を阻害するために、Nox、特にNox4の発現と関連する障害の処置に使用するための、本明細書中で前記に定めた式(I)の化合物が提供される。障害は、たとえば内分泌障害、心血管障害、呼吸器障害、代謝障害、皮膚障害、骨障害、神経炎症性障害、腎疾患、生殖障害、眼および/または水晶体を冒す疾患、ならびに/あるいは内耳を冒す状態、炎症性障害、肝疾患、痛み、癌、アレルギー性障害、外傷性障害、敗血症性、出血性およびアナフィラキシー性のショック、胃腸系の疾患または障害、異常な血管新生および血管新生依存性状態から選択できる。ある態様において、障害は糖尿病、発作、線維症、たとえば肺線維症、神経障害性疼痛、および糖尿病合併症、たとえば神経障害から選択される;たとえば障害は糖尿病であり、あるいは障害は発作である。
細胞ベースのアッセイおよび分析化学
1 細胞生存性
1.1 Celltiter−Blue細胞生存性アッセイ(Promega)
このアッセイは、生存性の尺度として細胞がレサズリン(resazurin)を還元してレゾルフィン(resorufin)にする能力に基づく。TREx(商標)−293 Nox4細胞をT−225フラスコ内で培養し、トリプシン処理により採集し、細胞培地に再懸濁した。90μl中20,000個の細胞を96ウェルの細胞培養プレート(透明な底を備えた黒色のもの)に播種した。90μlの細胞培地のみを含むバックグラウンドプレートも1つ用意した。
このアッセイは、膜の統合性の尺度としての周囲の細胞培地における乳酸デヒドロゲナーゼ(LDH)活性に基づく。膜の統合性はアポトーシス、ネクローシスまたは化学物質による影響を受ける可能性がある。TREx(商標)−293 Nox4細胞をT−225フラスコ内で培養し、トリプシン処理により採集し、HBSSに再懸濁して細胞100,000個/mlにした。90μlの細胞懸濁液をV底ポリプロピレン製96ウェルプレートの各ウェルに添加した。HBSSのみを含むバックグラウンドプレートを1つ用意した。化合物をHBSS中に最終濃度の10倍に希釈し、ウェル当たり10μlを添加した。化合物を10μMの最終濃度で二重に試験した。
[(実験量-自然量)/(総量-自然量)]*100%
上記2種類の細胞生存性アッセイで試験した場合、本発明化合物はいずれも有意の細胞毒性を示さなかった。
Amplex(登録商標)Redベースのアッセイによる用量応答測定を下記に従って実施した:化合物の系列希釈を、リキッドハンドラーJanus(登録商標)(Perkin Elmer)およびスケジューリングソフトウェアOverlord(Process Analysis and Automation)に基づくシステムを用いて実施した。
3 同一性、純度および安定性(IDENTITY, PURITY AND STABILITY)(IPS)分析
DMSO溶液を希釈して、PBS,pH7.4中、100μMの最終濃度にした。2つの試料を調製した:1つは即時分析のためのもの、2つ目は37℃で24時間保存するためのもの。
実施例2
Nox2に対する本発明化合物の活性
本発明化合物のNox4特異性を評価するために、多数の本発明化合物を、Nox2からの反応性酸素種(ROS)産生に対するそれらの潜在的な阻害効果について試験した。
PLB985細胞(ヒト急性骨髄性白血病細胞系)およびヒト末梢血単核細胞(peripheral blood mononuclear cell)(PBMC)について、ホルボール 12−ミリステート 13−アセテート(phorbol 12-myristate 13-acetate)(PMA)(30ng/ml)で刺激した後のNox2からのROS産生の阻害を、イソルミノール増強化学発光を用いて評価した。本発明化合物およびジフェニレンヨードニウムクロリド(diphenyleneiodonium chloride)(DPI)を、200μMから0,01μMまでの範囲の3倍希釈系列で用量設定した。
2 分析アッセイ
2.1 イソルミノールアッセイ
イソルミノール依存性化学発光(Dahlgren et al. 1999)を用いてROSのレベルを測定した。イソルミノールは生体膜を通過できない疎水性色素である。よって、この方法を用いて細胞外ROSを測定する。イソルミノールはROSにより励起され、励起された分子が基底状態に戻る際に発生する光を、放出されたROSの量に対比して測定する。この反応はペルオキシダーゼにより触媒および増幅される。天然のペルオキシダーゼがこれを達成できるが、それの分泌は限られており、よって追加のペルオキシダーゼ、この場合には西洋わさびペルオキシダーゼフラクションIIを添加する必要がある。
FluoStar Optima(BMG Labtech)および白色96ウェルプレートを用いて発光を検出した。37℃で振とうしながら67秒間、23サイクルの測定を実施した。これら23サイクルから曲線下面積(AUC)値を計算した。阻害剤を添加しなかったPMA刺激細胞と比較した変化率パーセントとして結果を評価した。非線形回帰およびIC50計算を、Mac OS X用のPrism 5を用いて実施した。
3.1 ヒトPBMC
人血(1日齢のバフィーコート中)をKomponentlab,Sahlgrenska University hospital,スウェーデン、ヨーテボリ(Goeteborg)から購入した。
赤血球を全血からデキストラン沈降により除去した。Ficoll−Paque Plus(0.75mg/mlのNaClを補足)を用い、製造業者の指示に従って、無赤血球画分を密度勾配遠心分離により分離した。PBMCを、血漿とFicoll−Paque Plus試薬の境界から単離した。混入血小板が除去されるまで、PBMCをHBSS中で洗浄した。細胞の数および生存率をトリパンブルー排除により判定した。
細胞をKreher et al. 2003に従って凍結保存した。簡単に述べると、単離した細胞を20×106個/mlで室温の凍結媒体A(60%のウシ胎仔血清,40%のRPMI 1640)に再懸濁した。等体積の室温の凍結媒体B(20%のDMSO,80%のウシ胎仔血清)を滴加した。15×106個の細胞を凍結チューブに分注し、予冷した(4℃)低温用速度制御凍結容器(Cryogenic Controlled-Rate Freezing Container)に入れて−80℃に置いた。24時間後、試料を不定期間保存のために−150℃のフリーザーへ移した。
細胞を37℃の水浴内で急速融解し、室温のHBSS中へピペッティングし、遠心分離した(250×g,20℃,5分)。HBSS中で洗浄した(2×)後、細胞をHBSSに2×106個/mlの濃度で再懸濁した。細胞の数および生存率をトリパンブルー排除により判定した。
3.1.4 細胞数:ヒトPBMC
総細胞数(バイアル当たり): 9〜9.75×106個
生存率: 92〜95%
アッセイ生存細胞濃度: 2×106個/ml
3.2 PLB985
PLB985細胞を、10%のウシ胎仔血清(FBS)およびペニシリン/ストレプトマイシン100U/mlを補足したRPMI 1640(=完全増殖培地)中、37℃、5% CO2で培養した。細胞をほぼ週2回、継代した。好中球と分別するために、細胞を遠心沈殿させ(250g,5分,室温)、1.25%のDMSOを補足した完全増殖培地に再懸濁して5日間おいた(Zhen et al.1993, Tucker et al.1987)。分析当日に、分別した細胞をペレット化し(250g,5分,室温)、HBSS中で2回洗浄し、HBSSに細胞2×106個/mlで再懸濁した。細胞の数および生存率をトリパンブルー排除により判定した。細胞を使用時まで室温に保存した。
総細胞数: 94×106個
生存率: 92%
アッセイ生存細胞濃度: 2×106個/ml
3.3 試薬
アッセイプレート,白色96ウェル(Nunc 236108)
デキストランT500(Pharmacosmos 5510 0500 4006)
DMSO(Sigma:D5879)
DPI
ウシ胎仔血清(VWR:LONZ14−801F)
Ficoll Paque Plus(GE Healthcare 71−7167−00)
fMLF(Sigma:F3506)
HBSS(自社調製:5.4mM KCl,0.3mM Na2HPO4×2H2O,0.4mM KH2PO4,4.2mM NaHCO3,1.3mM CaCl2×2H2O,0.5mM MgCl2×6H2O,0.6mM MgSO4×7H2O,137mM NaCl,5.6mM D−グルコース)
HRPフラクションII(Sigma P8250)
イソルミノール(4−アミノフタルヒドラジド)(Sigma A8264)
PMA(Sigma P8139)
RPMI 1640(VWR:LONZ12−702F/12)。
本発明化合物の100mM DMSO原液を試験に用いた。
3.5 イソルミノール緩衝液
イソルミノール緩衝液はイソルミノール(0,0175mg/ml)およびHRPフラクションII(1,75U/ml)を含有する。これらの成分を4×作業濃度でHBSS中に希釈することにより緩衝液を調製した。
4.1 物質調製
被験化合物をDMSO中に100×作業濃度で希釈し、最終濃度として200μMから0.01μMまで3倍希釈系列で用量設定した。
4.2 イソルミノールアッセイ
イソルミノール緩衝液中に4×作業濃度に希釈した25μlのPMAを各ウェルに添加した。非刺激対照ウェルにはイソルミノール緩衝液のみを添加した。その後、24μlのHBSSおよび1μlの化合物試験溶液またはDPI溶液のいずれかを試験プレートの各ウェルに添加した(最終DMSO濃度=1.25%)。最後に、50μlの細胞懸濁液(2x106個/ml)を各ウェルに添加し、続いて直ちに発光測定を開始した。
化合物2,4,6−トリメチル−N−フェネチルベンゼンスルホンアミドについての結果を、PMAの存在下での発光と比較した指定濃度の被験化合物の存在下で得られた発光%として表わす;図2を参照。
Claims (11)
- 式(I)の化合物
mは、1から3までの整数であり;
nは、0または1であり;
pは、0であり;
qは、2であり;
R1はそれぞれ、独立してC1−C3アルキル−X−から選択され;
Xはそれぞれ、独立して直接結合およびOから選択され;
R2は、独立してC1−C3アルキル−Y−、およびフェニル−(CH2)z−Y−から選択され;
Yは、Oであり;
zはそれぞれ、独立して0および1から選択される]
またはその医薬的に許容できる塩を含む、
内分泌障害、心血管障害、呼吸器障害、代謝障害、皮膚障害、骨障害、腎疾患、生殖障害、眼および/または水晶体を冒す疾患、ならびに/あるいは内耳を冒す状態、肝疾患、痛み、癌、アレルギー性障害、外傷性障害、敗血症性、出血性およびアナフィラキシー性のショック、胃腸系の疾患または障害、および異常な血管新生から選択される、ニコチンアミドアデニンジヌクレオチドリン酸オキシダーゼ4活性に関連する状態または障害の治療用の医薬組成物。 - R 1 はそれぞれ、メチルおよびメトキシから選択される、請求項1の組成物。
- nが0である、請求項1〜4のいずれか1項の組成物。
- 化合物が2,4,6−トリメチル−N−フェネチルベンゼンスルホンアミドである、請求項7の組成物。
- 障害が、糖尿病、脳卒中、線維症、たとえば肺線維症、神経障害性疼痛、および糖尿病合併症、たとえば神経障害から選択される、請求項1〜8の組成物。
- 障害が脳卒中である、請求項9の組成物。
- 障害が線維症である、請求項9の組成物。
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