JP2022530244A - Grk2タンパク質インヒビター化合物および同化合物を含む医薬組成物 - Google Patents
Grk2タンパク質インヒビター化合物および同化合物を含む医薬組成物 Download PDFInfo
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Abstract
Description
GRK2タンパク質は、「Gタンパク質共役受容体」(GPCR)として知られる膜受容体の大規模なファミリーの調節における重要なタンパク質キナーゼである。GRK2について説明される主な機能は、受容体が着実に刺激された場合の、それらの生理学的阻害である。この現象は「脱感作」として知られており、細胞に、必要に応じてGPCR依存性シグナリング経路を動的に不活性化できるようにさせる。GRK2タンパク質は、数ある中でも、アドレナリン、ヒスタミン、セロトニン、アセチルコリン、およびアンジオテンシンに対する細胞応答に関するGPCRの調節に関与する。よって、過剰なGRK2活性は無数の病態と関連しており、ならびにGRK2インヒビターを入手することは、これらの病態の薬理学的処置にとり有意義である。特に、このキナーゼが過剰に活性化されることが知られている心疾患の処置のためのGRK2インヒビターの調査において、多くの努力がなされてきた。しかしながら、インヒビターの調査は、GRK2を媒介したキナーゼ、または受容体のリン酸化活性を妨げることが可能な化合物を同定することに常に向けられてきた。今日、GRK2タンパク質は、受容体をリン酸化するだけでなく、そのRGSドメインを通して受容体とGタンパク質との間の相互作用(これによってGタンパク質を通し刺激が細胞中へ送られるかまたは伝えられて、生物学的応答が惹起される)を妨げることによって受容体を不活性化し得ることが知られている。本発明は、高い特異性および選択性でGRK2のRGSドメインの作用を阻害することが可能な新しいクラスの化合物の開発からなる。
本発明は、GRK2タンパク質インヒビター化合物に関する。特に、本発明は、式I
式中Xは、炭素および窒素から選択される原子であり、ならびに
R1は、基メチルカルボキシラートおよび1,3,4-オキサジアゾール-2-イルから選択される、
で表されるGRK2タンパク質インヒビター化合物に関し、ここで化合物は、メチル4-(ナフタレン-2-アミド)ベンゾアートおよびN-[4-(1,3,4-オキサジアゾール-2-イル)フェニル]キノリン-3-カルボキサミドから選択される。好ましい態様において、GRK2タンパク質インヒビター化合物は、メチル4-(ナフタレン-2-アミド)ベンゾアートである。
GRK2は、生理学的な関連性が大きいタンパク質であって、かつ無数の受容体の不活性化に関係するタンパク質であるので、その調節解除は、数ある中でも、高血圧、心不全、アルツハイマー病、リウマチ性関節炎、嚢胞性線維症、およびがんなどのさまざまな病態の発生に関連する。すべてのケースにおいて、受容体のシグナリング(各病態につき異なる)は、GRK2の過剰な活性化に起因して変化し、したがって、このタンパク質の阻害は病理学的症例の緩和またはその逆転をもたらすであろう。よって、今日まで、上述の病態の処置または制御に使用され得る新しいGRK2インヒビターを開発する必要がある。
で表されるGRK2タンパク質インヒビター化合物に言及する。特定のやり方において、本発明の化合物は、メチル4-(ナフタレン-2-アミド)ベンゾアートおよびN-[4-(1,3,4-オキサジアゾール-2-イル)フェニル]キノリン-3-カルボキサミドから選択される。好ましい態様において、GRK2タンパク質インヒビター化合物は、メチル4-(ナフタレン-2-アミド)ベンゾアートである。
さらに、本発明の別の対象は、該処置を必要とする罹患固体(patient)へ、少なくとも本発明の化合物の安全かつ有効な量を投与することを含む、GRK2細胞タンパク質によって媒介される、疾病の処置のための方法である。
しかしながら、本発明はまた、治療活性のある1以上の第2物質と組み合わせて、本発明の該化合物のうちの1以上を含む医薬組成物も包含する。
例1
メチル4-(2-ナフタミド)ベンゾアート(L96B)の合成
ステップa:4.0g(29.2mmol)の4-アミノ安息香酸を40mLのMeOH中に溶解した。この溶液を0℃まで冷却し、2.5当量のSOCl2を滴下し、それを激しく撹拌しながら2.5h還流した。次いで、溶媒を蒸発させ、それをNaHCO3飽和溶液(s.s.)で中和し、混合物をEtOAcで抽出した。有機相をNaCl s.s.で洗浄し、無水Na2SO4上で完全に乾燥させ(dried out)、溶媒を減圧にて蒸発させた。カラムクロマトグラフィー(n-ヘキサン/EtOAc)による粗残渣の精製によって、70%収率(3.1g)でメチル4-アミノベンゾアートを得ることができた。
M.P.:142℃
M+H+のためのMS(ESI)m/z:291.0890。
N-[4-(1,3,4-オキサジアゾール-2-イル)フェニル]キノリン-3-カルボキサミド(L94C)の合成
メチル4-(キノリン-3-カルボキサミド)ベンゾアート(L94A)を、例1において説明したのと同様の手順に倣うが、ステップbにおいて3-キノリンカルボン酸を使用して得た。
M.P.:202℃
M+H+のためのMS(ESI)m/z:317.10390。
Gαs-アデニル酸シクラーゼ-cAMPルートに関連する受容体の応答に対するインヒビターの増強効果
本発明の化合物の、およびエナミンライブラリからの以下の化合物の阻害活性を研究した:
本発明による化合物
L96B:メチル4-(ナフタレン-2-アミド)ベンゾアート
L94C:N-[4-(1,3,4-オキサジアゾール-2-イル)フェニル]キノリン-3-カルボキサミド
C4:3-(ナフタレン-2-イル)-1-[3-(1H-ピラゾール-1-イル)ピペリジン-1-イル]プロパン-1-オン
C2:3-(1-アセチル-2,3-ジヒドロ-H-インドール-5-イル)-1-(キノリン-8-イル)ウレア
C3:2,7-ジメチル-N-[3-(1,3,4-オキサジアゾール-2-イル)フェニル]キノリン-3-カルボキサミド
C5:2-(4-オキソ-3,4-ジヒドロフタラジン-1-イル)-N-(キノリン-5-イル)アセトアミド
C10:N-(2,3-ジヒドロ-1H-インデン-1-イル)-3-[5-(4-メチルフェニル)-1,3,4-オキサジアゾール-2-イル]プロパンアミド
サンプル中のcAMPを、Davio et al, 1995に従って架橋タンパク質結合法(linking protein-binding technique)を適応させることによって定量化した。
インヒビター効果の選択性
GRK2のRGSドメインに対する化合物の効果の特異性を査定するために、rH2およびGRK2K220R/R106A(RGSドメインを通してキナーゼ活性と脱感作作用との両方を欠くGRK2二重突然変異体ドミナントネガティブ構成物)を過剰発現する第2系においてアッセイを実施した。このケースにおいて、GRK2の不活性バリアントの過剰発現は、rH2応答の調節を防止する。RGSドメインを不活性化するR106A突然変異は、潜在的な阻害力(inhibitory potential)という効果に対しては不必要であり、よって、モデルの選択性制御を構成し、ならびにレシーバー応答における増強がRGSドメインの阻害の結果として生じたのか、またはそれが不要な標的に対する化合物の非特異的作用の結果であったのかを決定できるようにする。この制御系においてもまたcAMPレベルを上昇させるこれらの化合物は、非特異的作用があると見なされる。
400,000個の細胞をウシ胎児血清なしで2時間飢餓状態にし、最小培地(RPMI)中100nMおよび10μMの濃度にて本発明の化合物L96BおよびL94Cで、37℃にて40min前処置した。同等量のビヒクル(DMSO)を陰性対照として使用した。
サンプル中のcAMPを、Davio et al, 1995に従って架橋タンパク質結合法を適応させることによって定量化した。
白血病細胞分化に対するインヒビターの効果
細胞分化の誘導は、細胞成熟を達成させ、また白血病細胞の増殖を遅らせるのに所望される事象である。このプロセスは、異なる刺激に応答して第2のcAMPメッセンジャーの生成と密接に関する。U937白血病細胞の分化に対する化合物の効果を、ヒスタミン(cAMP細胞内レベルを増大させる剤であるが、cAMPシグナルは、GRK2によるヒスタミン受容体の急速な脱感作に起因して、細胞分化を誘導するには不十分である)と、化合物C2およびC10と、本発明による化合物L96Bとの混合(joint)処置後、CD88単球に対し最終分化マーカーの発現を測定することによって研究した。
β-アドレナリンアゴニスト(イソプロテレノール)で刺激された心筋細胞のcAMP応答に対する本発明の化合物の効果
B-アドレナリン受容体は、心筋の強度および収縮性を制御するのを担う。これらの受容体の機能はGRK2によってモジュレートされており、GRK2によるそれらの脱感作は、高血圧症または心不全を持つ罹患個体において亢進されている。
その後、細胞を溶解し、無水エタノール中に再懸濁した。これを蒸発させ、cAMPレベルを決定した。サンプル中のcAMPを、Davio et al,1995に従って架橋タンパク質結合法を適応させることによって定量化した。
不死化されたヒト肝細胞の生存率に対する本発明の化合物の効果
創薬プロセスの30パーセントは化合物の予想外の毒性に起因して不成功に終わる。肝毒性は、薬剤が身体に影響を及ぼす毒性の主な形態の1つであるので、インヒビターの細胞毒性を、ヒト肝細胞HEPG2細胞株を使用して査定した。
Claims (9)
- 請求項1に記載のGRK2タンパク質インヒビター化合物および薬学的に許容し得る賦形剤を少なくとも含む、医薬組成物。
- 請求項2に記載のGRK2タンパク質インヒビター化合物および薬学的に許容し得る賦形剤を含む、医薬組成物。
- 請求項3に記載のGRK2タンパク質インヒビター化合物および薬学的に許容し得る賦形剤を含む、医薬組成物。
- 請求項2および3のいずれか一項に記載のGRK2タンパク質インヒビター化合物および抗腫瘍剤を少なくとも含む、医薬組成物。
- 組成物が、経口、非経口、または経皮経路を介して投与されてもよい医薬組成物である、請求項4~7のいずれか一項に記載の医薬組成物。
- 組成物が、がん、高血圧症、心不全、炎症性疾患、アルツハイマー病(AD)、リウマチ性関節炎、嚢胞性線維症(CF)、敗血症、および多発性硬化症(MS)の処置および/または制御に有用である、請求項4~7のいずれか一項に記載の医薬組成物。
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Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240612 |