JP2019534893A - Cxcr4アンタゴニストおよび使用方法 - Google Patents
Cxcr4アンタゴニストおよび使用方法 Download PDFInfo
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- JP2019534893A JP2019534893A JP2019533297A JP2019533297A JP2019534893A JP 2019534893 A JP2019534893 A JP 2019534893A JP 2019533297 A JP2019533297 A JP 2019533297A JP 2019533297 A JP2019533297 A JP 2019533297A JP 2019534893 A JP2019534893 A JP 2019534893A
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
Description
式−[C(=O)]a−[R1a]b−Ar1a(式中、aとbのいずれか一方が1であれば、aとbは0か1のいずれかであり、R1aはアルキレンであり、Ar1aは任意に置換されたアリールである)の部分;X1は、Arg、Dap、Dab、Orn、Lys、Dap(iPr)、Dab(iPr)、Orn(iPr)、またはLys(iPr)である;X2は、Arg、Dap、Dab、Orn、Lys、Dap(iPr)、Dab(iPr)、Orn(iPr)、Lys(iPr)、D−Arg、D−Dap、D−Dab、D−Orn、D−Lys、D−Dap(iPr)、D−Dab(iPr)、D−Orn(iPr)、D−Lys(iPr)または不存在である;X3はGly、Lys、Lys(アシル)または不存在である;X4はPhe、2Nal、1Nal、またはその(D)異性体または不存在である;X5はGlyまたは不存在である;R2は−OHまたは−NHR4であって、R4はH、C1−18アルキル、任意に置換されたC6−24アリール、または任意に置換されたアラルキルである。
ある特定の態様において、Ar1は1,2−置換フェニルであり、すなわち−CH2− 基は互いに対して1,2−位で置換されている。
次の式の化合物は、
この化合物は次の式によっても表すことができる:
表1:例示されたペプチドの特徴付けおよび結合活性
1. 細胞を10%FBSを添加したDME/F12またはRPMI1640培地中で増殖させた。
2. 細胞を、24時間後に増殖細胞が単層としておよそ80〜90%コンフルエントに達するような密度で96ウェル組織培養プレート上に播種した。(MDA−MB−231:50000/ウェル;HCC1806:40000/ウェル;A549:50000/ウェル)
3. 細胞を2時間飢餓状態にした(無血清培地(SFM)で培養した)。Essen BioScience, Inc.によって提供される創傷メーカーを使用して各ウェルに引っ掻き傷を付けた。次いでプレートをPBSで2回洗浄した。
4. 細胞を、100μlの無血清培地(SFM)中のDMSO(対照)またはペプチドCXCR4−アンタゴニスト(200nmol/L)で2時間前処理した。
5. 次に、培地を、DMSOまたはペプチドCXCR4−アンタゴニスト(200nmol/L)と組み合わせたリガンドSDF−1α(100ng/ml)の有無にかかわらず、新鮮なSFM(100μl)と交換した。
6. 次にプレートをIncuCyteシステムに入れ、通常の細胞培養インキュベーターで1〜2日間インキュベートした。4時間毎にIncuCyteスキャンによって得られたデータをIncuCyteソフトウェアによって分析し、そして創傷治癒曲線を作成した。
アッセイデータは図1〜4に報告される。図1は、本発明の化合物が、TNBCMDA−MB−231細胞におけるリガンド(SDF−1α)誘導細胞遊走を阻害できたことを示す。MDA−MB−231細胞は上記の細胞遊走アッセイにより分析した。200ng/mlのSDF−1αを使用した。 使用した本発明の化合物(例えば、MLB−009、MLB−010、MLB−014、およびMLB−011)の濃度は200nmol/Lであった。0時間の緑色は最初のスクラッチ領域を示し;12時間または16時間で、緑色は細胞遊走のない残りの領域を示す。図2は、図1に記載のMDA−MB−231細胞に対する細胞遊走アッセイの定量化である。図3は、本発明の化合物がSDF−1α誘導HCC1806細胞遊走も阻害することを示す。別のTNBCHCC1806細胞株を細胞遊走アッセイを用いて分析した。100ng/mlのSDF−1αを使用した。使用した化合物(MLB−009、MLB−010、MLB−014、およびMLB−011)の濃度は200nmol/Lであった。0時間の緑色は最初のスクラッチ領域を示し;12時間で、緑色は細胞遊走のない残りの領域を示す。図4は、図3に記載のHCC1806細胞遊走アッセイの定量化である。
1. SFMで1:100に希釈したマトリゲルを96ウェル組織培養プレート(50μl/ウェル)に加えた。該プレートを通常の細胞培養インキュベーターに一晩置いた。
2. 10%FBSを添加したDME/F12またはRPMI1640培地中で増殖させた細胞を上記の96ウェルプレート上に播種した。(MDA−MB−231:50000/ウェル;HCC1806:40000/ウェル;A549:50000/ウェル)
3. 翌日、細胞を2時間飢餓状態にした(SFMで培養した)。IncuCyte機器を介した創傷メーカーを使用して各ウェルに引っ掻き傷を付けた。次いでプレートをPBSで2回洗浄した。
4. 細胞を、100μlのSFM中のDMSO(対照)または本発明の化合物(200nmol/L)で2時間前処理した。
5. 次に、細胞培養培地を、1:20の比(50μl/ウェル)でSFMで希釈したマトリゲルと交換した。該プレートをインキュベーターに1時間静置した。
6. SDF−1α(100ng/ml)+DMSOまたは本発明の化合物(200nmol/L)を含むかまたは含まない新鮮なSFM(100μl)を96ウェルプレートの各ウェルに添加した。
7. 次に該プレートをIncuCyteシステムに入れ、通常の細胞培養インキュベーターで1〜2日間インキュベートした。4時間毎にIncuCyteスキャニングを通して得られたデータをIncuCyteソフトウェアにより分析し、そして細胞浸潤曲線を作成した。
そのデータは図5〜7で報告される。図5は、MDA−MB−231細胞に対する細胞浸潤アッセイの定量化である。図6は、HCC1806細胞に対する細胞浸潤アッセイの定量化である。図7は、NSCLCA549細胞に対する細胞浸潤アッセイの定量化である。
Relative Wound Density (Percent) 相対創傷密度(パーセント)
Time (Hours) 時間(時間)
Claims (22)
- 次の式の化合物またはその薬学的に許容される塩:
aは0または1;
AA1はそれに結合しているイオウ原子と共に、3−メルカプトプロピオン酸、任意に置換されたシステイン、または任意に置換されたホモシステイン;
AA2はそれに結合しているイオウ原子と共に、システインまたはホモシステイン;
Ar1は任意に置換されたアリール;
X1は、Arg、Dap、Dab、Orn、Lys、Dap(iPr)、Dab(iPr)、Orn(iPr)、またはLys(iPr);
X2は、Arg、Dap、Dab、Orn、Lys、Dap(iPr)、Dab(iPr)、Orn(iPr)、Lys(iPr)、D−Arg、D−Dap、D−Dab、D−Orn、D−Lys、D−Dap(iPr)、D−Dab(iPr)、D−Orn(iPr)、D−Lys(iPr)または不存在;
X3はGlyまたは不存在;
X4はPhe、2Nal、1Nalまたは不存在;
X5はGlyまたは不存在;
R2は−OR4または−NHR5;
R4はHまたはアルキル;および
R5はH、アルキル、任意に置換されたアリール、任意に置換されたアラルキルである。 - 次の式の請求項1に記載の化合物またはその薬学的に許容される塩:
aは0または1;
mおよびnは独立して1または2;
R1はHまたは−NHR3であって、R3はH、アルキル、アシル、任意に置換されたアリール、任意に置換されたアラルキル、−C(=O)−Araであって、Araは任意に置換されたアリール;および
Ar1、X1、X2、X3、X4、X5およびR2は請求項1に定義されているものである。 - 薬学的に許容される塩は酢酸塩、塩酸塩、またはトリフルオロ酢酸塩である、請求項1または2に記載の化合物。
- a=1およびAr1は任意に置換されたフェニルである、請求項1〜3のいずれか1項に記載の化合物。
- m=1およびn=1である、請求項1〜4のいずれか1項に記載の化合物。
- m=1およびn=2である、請求項1〜4のいずれか1項に記載の化合物。
- m=2およびn=1である、請求項1〜4のいずれか1項に記載の化合物。
- X2は、 (D)−異性体または不存在である、請求項1〜7のいずれか1項に記載の化合物。
- X4は、 (D)−異性体または不存在である、請求項1〜8のいずれか1項に記載の化合物。
- R1はHおよびm=1である、請求項1〜9のいずれか1項に記載の化合物。
- R1はAc−NHおよびm=2である、請求項1〜9のいずれか1項に記載の化合物。
- R2は−NH(Et)およびX4とX5は不存在である、請求項1〜11のいずれか1項に記載の化合物。
- 配列番号4〜28からなる群から選択される、請求項1に記載の化合物。
- m=1、n=1およびR1はNHR3であって、R3は請求項2で定義されるものである、請求項1〜5のいずれか1項に記載の化合物。
- m=1、n=2およびR1はNHR3であって、R3は請求項2で定義されるものである、請求項1〜4のいずれか1項に記載の化合物。
- m=2、n=1およびR1はNHR3であって、R3は請求項2で定義されるものである、請求項1〜4のいずれか1項に記載の化合物。
- 請求項1の化合物またはその薬学的に許容される塩、および薬学的に許容される賦形剤を含む医薬組成物。
- 薬学的に許容される賦形剤は、薬学的に許容される担体、希釈剤、賦形剤、結合剤、香味剤、またはそれらの組合せを含む、請求項17に記載の医薬組成物。
- CXCR4活性化に関連する臨床状態を被っている対象を治療する方法であって、前記方法は請求項1〜16のいずれか1項に記載の化合物の治療有効量を治療が必要な対象に投与することを含む、方法。
- 前記臨床状態は関節リウマチ、肺線維症、HIV感染、または癌を含む、請求項19に記載の方法。
- 前記癌は、乳癌、膵臓がん、黒色腫、前立腺がん、腎がん、神経芽細胞腫、非ホジキンリンパ腫、肺がん、卵巣がん、結腸直腸がん、多発性骨髄腫、多形神経膠芽腫、および慢性リンパ性白血病からなる群から選択される、請求項20に記載の方法。
- 関節リウマチ、肺線維症、HIV感染、または癌を有する患者の治療方法であって、前記方法は請求項1〜16のいずれか1項に記載の化合物の治療有効量を治療が必要な対象に投与することを含む、方法。
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