JP2021073253A - Hdac6阻害剤での多嚢胞性疾患の治療 - Google Patents
Hdac6阻害剤での多嚢胞性疾患の治療 Download PDFInfo
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
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Abstract
Description
本出願は、2013年10月24日に出願のU.S. Provisional Application No. 61/895,223に対する優先権及びそれの利益を主張し、その全体が参照により本明細書に援用される。
本開示は、多嚢胞性疾患の治療のためのHDAC6阻害剤の投与について報告する。
本発明は、国立衛生研究所(NIH)によって授与されるP30DK084567、R21CA166635及びR01 DK24031の元で政府支援により行われた。政府は、本発明において一定の権利を有する。
HDAC6の小分子阻害剤、その医薬組成物及びこれらの化合物を使用して多嚢胞性疾患を治療する方法が、本明細書において提供される。
式中、環Bは、アリールまたはヘテロアリールであり、R1はアリールまたはヘテロアリールであり、そのそれぞれはOH、ハロまたはC1−6−アルキルによって任意に置換されてもよく、及びRはHまたはC1−6−アルキルであり、及び式Iのヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の量は、被験体における嚢胞成長を減少させるのに有効である、方法を提供する。
式中、Xは、CまたはOであり;
Ryは、存在ごとに、C1−6−アルキル、C1−6−アルコキシ、ハロ、−C1−6ハロアルキル、−C1−6ジハロアルキル、−C1−6トリハロアルキル、−OH、−N(R1)2、−C(O)R1、−CO2R1及び−C(O)N(R1)2からなる群から独立して選択される;
または:
同じまたは隣接した炭素原子上の2つのRy基は、共になってC3−8−シクロアルキルまたはC3−7−ヘテロシクロアルキル環を形成し、そのそれぞれは縮合しても、または分離してもよく;
Rzは、存在ごとに、C1−6−アルキル、C1−6−アルコキシ、ハロ、−C1−6ハロアルキル、−C1−6ジハロアルキル、−C1−6トリハロアルキル、−OH、−N(R2)2、−C(O)R2、−CO2R2、−C(O)N(R2)2からなる群から独立して選択され;
それぞれのR1は、存在ごとに、H、C1−6−アルキル、C3−8−シクロアルキル、C3−7−ヘテロシクロアルキル、アリール、ヘテロアリール、C1−6−アルキル−シクロアルキル、C1−6−アルキル−ヘテロシクロアルキル、C1−6−アルキル−アリール及びC1−6−アルキル−ヘテロアリールからなる群から独立して選択され;
それぞれのR2は、存在ごとに、HまたはC1−6−アルキルからなる群から独立して選択され;
mは、0、1、2または3であり;及び
nは、0、1、2または3であり、
及び式IIのヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の量は、被験体における嚢胞成長を減少させるのに有効である、方法を提供する。
またはその薬学的に許容される塩、
または:
またはその薬学的に許容される塩、である。
本発明を記述するのに使用される種々の用語の定義を下に収載する。これらの定義は、個々に、またはより大きな群の部分としてのいずれかに、特定の例において限定されない限り、これらが本明細書及び特許請求の範囲の全体にわたって使用されるときに、該用語に適用される。
いくつかの実施形態において、HDAC6特異的阻害剤は、式Iの化合物:
式中、
環Bは、アリールまたはヘテロアリールであり;
R1は、アリールまたはヘテロアリールであり、そのそれぞれは、OH、ハロまたはアルキルによって任意に置換されてもよく;
及び
Rは、Hまたはアルキルである。
Xは、CまたはOであり;
Ryは、存在ごとに、C1−6−アルキル、C1−6−アルコキシ、ハロ、−C1−6ハロアルキル、−C1−6ジハロアルキル、−C1−6トリハロアルキル、−OH、−N(R1)2、−C(O)R1、−CO2R1及び−C(O)N(R1)2からなる群から独立して選択される;
または:
同じまたは隣接した炭素原子上の2つのRy基は、共になってC3−8−シクロアルキルまたはC3−7−ヘテロシクロアルキル環を形成し、そのそれぞれは、縮合されても、または分離されてもよく;
Rzは、存在ごとに、C1−6−アルキル、C1−6−アルコキシ、ハロ、−C1−6ハロアルキル、−C1−6ジハロアルキル、−C1−6トリハロアルキル、−OH、−N(R2)2、−C(O)R2、−CO2R2、−C(O)N(R2)2からなる群から独立して選択され;
それぞれのR1は、存在ごとに、H、C1−6−アルキル、C3−8−シクロアルキル、C3−7−ヘテロシクロアルキル、アリール、ヘテロアリール、C1−6−アルキル−シクロアルキル、C1−6−アルキル−ヘテロシクロアルキル、C1−6−アルキル−アリール及びC1−6−アルキル−ヘテロアリールからなる群から独立して選択され;
それぞれのR2は、存在ごとに、HまたはC1−6−アルキルからなる群から独立して選択され;
mは、0、1、2または3であり;及び
nは、0、1、2または3である。
本発明の1つの態様において、本明細書において記述したように、その必要のある被験体に式IまたはIIのHDAC6特異的阻害剤化合物の治療上有効な量を投与することを含む多嚢胞性疾患の治療のための方法が提供される。
HDAC6特異的阻害剤化合物A−1の量は、嚢胞成長を阻害するのに有効である、方法が提供される。
HDAC6特異的阻害剤化合物B−1の量は、嚢胞成長を阻害するのに有効である、方法が提供される。
HDAC6特異的阻害剤化合物C−2の量は、嚢胞成長を阻害するのに有効である、方法が提供される。
もう一つの態様において、本発明は、式IもしくはIIの化合物またはそれらの薬学的に許容されるエステル、塩またはプロドラッグを含む医薬組成物を薬学的に許容される担体と共に提供する。この医薬組成物は、多嚢胞性疾患の治療において使用されることができる。
本明細書における開示は、被験体における多嚢胞性疾患を治療するための式IまたはIIの異なる用量の化合物を有するパッケージユニットを含むキット形式を提供する。一定の実施形態において、式Iの化合物は、化合物A−1または化合物B−1である。その他の実施形態において、式IIの化合物は、化合物C−2である。
式Iの化合物の合成は、PCT/US2011/021982において提供され、その全体が参照により本明細書に援用される。
DMSO(690ml)中の化合物2(69.2g、1当量)、1−クロロ−2−ヨードベンゼン(135.7g、2当量)、Li2CO3(42.04g、2当量)、K2CO3(39.32g、1当量)、Cu(1当量45μm)の混合物を窒素でガス抜きし、及び除去した。生じる混合物を140℃で撹拌した。反応のワークアップは、93%収量にて化合物3を与えた。
上の化合物A−1の合成を参照されたい。
試験のための化合物を50倍の終濃度までDMSO中に希釈し、及び10.3倍希釈シリーズを作製した。化合物をアッセイ緩衝液(50mM HEPES、pH7.4、100mM KCl、0.001% Tween−20、0.05% BSA、20μM TCEP)中に6倍のこれらの終濃度まで希釈した。HDAC酵素(BPS Biosciencesから購入した)をアッセイ緩衝液中に1.5倍のこれらの終濃度まで希釈した。0.05μM終濃度にてトリペプチド基質及びトリプシンを6倍のこれらの終濃度でアッセイ緩衝液中に希釈した。これらのアッセイにおいて使用される最終酵素濃度は、3.3ng/ml(HDAC1)、0.2ng/ml(HDAC2)、0.08ng/ml(HDAC3)及び2ng/ml(HDAC6)であった。使用される最終基質濃度は、16μM(HDAC1)、10μM(HDAC2)、17μM(HDAC3)及び14μM(HDAC6)であった。
ポリメラーゼ連鎖反応
RNAをTRIZOL試薬(Invitrogen)で対照及びPCKラット胆管細胞から単離した。cDNAをFirst Srand cDNA Synthesis(Invitrogen)試薬を使用して得て、及びHDAC6プライマー(フォワードプライマー:5’−TCA GCG CAG TCT TAT GGA TG−3’(配列番号:1);リバースプライマー:5’−GCG GTG GAT GGA GAA ATA GA−3’、配列番号:2)をIntegrated DNA Technologiesから購入した。β−カテニンmRNA発現を製造業者の指導に従ってTaqMan Gene Expression Assay(アッセイID Rn00584431_g1)を使用して解析した。試料を18S rRNAに規準化した。
培養された対照ラット及びPCKラット胆管細胞から単離されるタンパク質を解析した。細胞を破片にし、プロテアーゼ阻害剤、バナジン酸ナトリウム及びフッ化フェニルメチルスルホニル(PMSF)とリン酸緩衝食塩水(PBS)中に再懸濁し、超音波処理し、試料タンパク質の同等の量をLaemmli Sample Buffer(Biorad)及びメルカプトエタノール中に希釈した。SDSポリアクリルアミドゲル電気泳動、SDS−PAGEの後、タンパク質をニトロセルロース膜へ移し、ブロックし、及び次いで、以下の一次抗体とインキュベートした:HDAC6(Santa Cruz Biotechnology、D−11、1:500)、アセチル化−α−チューブリン(Sigma Aldrich、1:2000)、β−カテニン(Cell Signaling Technology、(D10A8)XP(登録商標)Rabbit mAb; 1:1000)、ホスホ−β−カテニン(Ser33/37/Thr41)(Cell Signaling Technology、1:1000)、アセチル−β−カテニン(Cell Signaling Technology、1:1000)、c−myc(Santa Cruz Biotechnology、1:500)、サイクリンD1(Santa Cruz Biotechnology、1:500)及びアクチン(Sigma Aldrich、1:5000)。膜を4℃で一晩インキュベートし、洗浄し、及び西洋ワサビペルオキシダーゼ抱合された(1:5000、Invitrogen)またはIRdye 680もしくは800(1:15000、Odyssey)対応二次抗体と室温で1時間インキュベートした。ECLシステムまたはOdyssey Licor Scannerをタンパク質検出のために使用し、及びGel−Pro Analyzer 6.0ソフトウェアをデンシトメトリー解析のために使用した。
データを平均±SEとして表す。統計分析を両側によって行った;スチューデントt検定を2つの群を比較するのに使用した。有意性のためのカットオフp値は、p<0.05にてセットした。
インビトロ実験について、胆管細胞を対照ラット、PCKラット(an animal model for ARPKD; Vroman B, LaRusso NF: Development and characterization of polarized primary cultures of rat intrahepatic bile duct epithelial cells, Lab Invest 1996, 74:303−313)、健康なヒト及びADPKD患者(Masyuk et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia, Am J Physiol Gastrointest Liver Physiol (2010) 299:G990−999; O’Haraet al. Cholangiocyte N−Ras protein mediates lipopolysaccharide−induced interleukin 6 secretion and proliferation, J Biol Chem (2011) 286:30352−30360; Banaleset al. Up−regulation of microRNA 506 leads to decreased Cl(−)/HCO(3) (−) anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis, Hepatology (2012) 56(2):687−97)から単離した。
対照及びPCKラット胆管細胞をNRC Mediaを使用してCollagen−I被覆フラスコ(BD Biocoat)において培養し、0.25% Trypsin−EDTA(GIBCO)で剥離させ、Collagen−I被覆96ウェルプレート(10000細胞/ウェル)へ移し、及び37℃、5% CO2、100%湿度にてインキュベートした。NRC培地中に懸濁される5、10及び20μmol/LツバスタチンA(Chemie Tek)、1−2μmol/Lツバシン(Chemie Tek)または2、4及び8μmol/L化合物A−1(Acetylon Pharmaceutical Inc)での治療を24時間後に始めた。薬物媒体、DMSOを対照としてNRC Media中に懸濁した。細胞増殖をCellTiter 96 AQueous One Solution(MTS;Promega)で評価し、及び/またはCellometer Auto T4 Cell Counter(Nexcelom Bioscience)を使用して細胞を計数した。
PCKラットから新たに単離された胆管をラット尾部I型Collagenマトリックス(BD Biosciences)中に包埋し、10μmol/LツバスタチンA及び2μmol/Lツバシンの存在または非存在下で成長させた。成長する嚢胞の画像を5日間にわたって毎日撮影し、及び嚢胞サイズをソフトウェア「Image J」(National Institute of Health)で測定した。それぞれの嚢胞性構造についての周囲領域を前述したように0日目と比較して成長の割合を算出した(Muff et al. Development and characterization of a cholangiocyte cell line from the PCK rat, an animal model of Autosomal Recessive Polycystic Kidney Disease, Lab Invest 2006, 86:940−950; Masyuk et al. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3’,5’−cyclic monophosphate, Gastroenterology (2007) 132:1104−1116 27; Leeet al. MicroRNA15a modulates expression of the cell−cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease, J. Clin. Invest. (2008) 118:3714−3724 28. Gradilone et al. Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD, Gastroenterology (2010) 139:304−314 e302を参照されたい)。
PCK胆管細胞増殖の阻害及び3D培養における嚢胞成長の原因である機構のより優れた知識のために、培養されたPCK胆管細胞をツバスタチン−A及びツバシンで処理し、及びアセチル化α−チューブリン及びβ−カテニンの量をウェスタンブロッティングによって決定した。
この動物における遺伝子組換えが、ヒトARPKDにおいて見いだされたものにオルソロガスであるので、PCKラットモデルを使用した。これらの動物は、ヒトADPKDの特徴の多くを発現する(Lager DJ, et al., Kidney Internat 59: 126−136, 2001; Harris, Curr Opin Nephrol Hypertens 11:309−314, 2002)。この突然変異をもつ動物は、腎臓及び肝臓の両方の線維嚢胞性疾患を示し、及びこれらの動物は、長期の治療プロトコルを容易にするのに十分に長く生きる(Gattone V.H., et al., Nat Med (2003) 9: 1323− 1326; Torres V.E., et al., Nat Med (2004) 10:363−364; Masyuk T.V., et al., Gastroenterology (2007) 132:1104−1116, 2007)。雌動物は、雄動物より重篤な肝疾患を示す。
雄PKC−1ラット(4週間目、n=12)を12週間化合物の示した用量で1日1回経口経管栄養によって処理した。動物を殺し、及び腎臓を除去し、及びホルマリン中に固定した。腎臓における嚢胞の容積を組織学的解析によって測定した(図7を参照されたい)。比較として、6匹のラットを4週間で殺して、腎嚢胞の開始容積を測定した(対照)。
Claims (23)
- 多嚢胞性疾患を治療するための方法であって:
式I:
式中、
環Bは、アリールまたはヘテロアリールであり;
R1はアリールまたはヘテロアリールであり、そのそれぞれはOH、ハロまたはC1−6−アルキルによって任意に置換されてもよく;
及び
Rは、HまたはC1−6−アルキルであるか、
または
式II:
式中、
Xは、CまたはOであり;
Ryは、存在ごとに、C1−6−アルキル、C1−6−アルコキシ、ハロ、−C1−6ハロアルキル、−C1−6ジハロアルキル、−C1−6トリハロアルキル、−OH、−N(R1)2、−C(O)R1、−CO2R1及び−C(O)N(R1)2からなる群から独立して選択される;
または:
同じまたは隣接した炭素原子上の2つのRy基は、共になってC3−8−シクロアルキルまたはC3−7−ヘテロシクロアルキル環を形成し、そのそれぞれは縮合しても、または分離してもよく;
Rzは、存在ごとに、C1−6−アルキル、C1−6−アルコキシ、ハロ、−C1−6ハロアルキル、−C1−6ジハロアルキル、−C1−6トリハロアルキル、−OH、−N(R2)2、−C(O)R2、−CO2R2、−C(O)N(R2)2からなる群から独立して選択され;
それぞれのR1は、存在ごとに、H、C1−6−アルキル、C3−8−シクロアルキル、C3−7−ヘテロシクロアルキル、アリール、ヘテロアリール、C1−6−アルキル−シクロアルキル、C1−6−アルキル−ヘテロシクロアルキル、C1−6−アルキル−アリール及びC1−6−アルキル−ヘテロアリールからなる群から独立して選択され;
それぞれのR2は、存在ごとに、HまたはC1−6−アルキルからなる群から独立して選択され;
mは、0、1、2または3であり;及び
nは、0、1、2または3である、
を多嚢胞性疾患をもつ被験体に投与することを含む、前記方法。 - 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、前記被験体における嚢胞成長を減少させるのに有効である、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記多嚢胞性疾患は、多嚢胞肝である、前記方法。
- 請求項2に記載の多嚢胞性疾患を治療するための前記方法であって、前記嚢胞は、肝臓に位置する、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記多嚢胞性疾患は、嚢胞性腎疾患である、前記方法。
- 請求項5に記載の多嚢胞性疾患を治療するための前記方法であって、前記嚢胞性腎疾患は、多発性嚢胞腎である、前記方法。
- 請求項2に記載の多嚢胞性疾患を治療するための前記方法であって、前記嚢胞は、腎臓に位置する、前記方法。
- 請求項5に記載の多嚢胞性疾患を治療するための前記方法であって、前記嚢胞性腎疾患は、常染色体優性多発性嚢胞腎(ADPKD)である、前記方法。
- 請求項5に記載の多嚢胞性疾患を治療するための前記方法であって、前記嚢胞性腎疾患は、常染色体劣性多発性嚢胞腎(ARPKD)である、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、嚢胞の前記形成を防ぐのに有効である、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管細胞増殖を阻害するのに有効である、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管アセチル化チューブリンの前記量を増加させるのに有効である、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管β−カテニン合成を減少させるのに有効である、前記方法。
- 請求項1に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管β−カテニンリン酸化及び/またはアセチル化を増加させるのに有効である、前記方法。
- 請求項15に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、前記被験体における嚢胞成長を減少させるのに有効である、前記方法。
- 請求項15に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管細胞増殖を阻害するのに有効である、前記方法。
- 請求項18に記載の多嚢胞肝を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、前記被験体における嚢胞成長を減少させるのに有効である、前記方法。
- 請求項18に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管細胞増殖を阻害するのに有効である、前記方法。
- 請求項21に記載の多嚢胞肝を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、前記被験体における嚢胞成長を減少させるのに有効である、前記方法。
- 請求項21に記載の多嚢胞性疾患を治療するための前記方法であって、前記ヒストンデアセチラーゼ6(HDAC6)特異的阻害剤化合物の前記量は、胆管細胞増殖を阻害するのに有効である、前記方法。
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EP3060217A1 (en) | 2016-08-31 |
EP3060217B1 (en) | 2022-06-08 |
US20150119413A1 (en) | 2015-04-30 |
US20210161891A1 (en) | 2021-06-03 |
US20240091225A1 (en) | 2024-03-21 |
HK1225964A1 (zh) | 2017-09-22 |
EP4137135A1 (en) | 2023-02-22 |
US11666569B2 (en) | 2023-06-06 |
JP2023093669A (ja) | 2023-07-04 |
ES2918673T3 (es) | 2022-07-19 |
EP3060217A4 (en) | 2017-04-12 |
JP2016534069A (ja) | 2016-11-04 |
US10660890B2 (en) | 2020-05-26 |
WO2015061684A1 (en) | 2015-04-30 |
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