JP2019528289A - ミノキシジルとペプチドの結合体 - Google Patents
ミノキシジルとペプチドの結合体 Download PDFInfo
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- JP2019528289A JP2019528289A JP2019510337A JP2019510337A JP2019528289A JP 2019528289 A JP2019528289 A JP 2019528289A JP 2019510337 A JP2019510337 A JP 2019510337A JP 2019510337 A JP2019510337 A JP 2019510337A JP 2019528289 A JP2019528289 A JP 2019528289A
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Abstract
Description
また、本発明は、前記で開示されたいずれか一つの化合物を含有する脱毛防止又は発毛促進用の薬学的組成物を提供する。
但し、下記実施例及び実験例は本発明を例示するためのものにすぎず、本発明の内容が下記実施例及び実験例によって限定されるものではない。
クロロトリチルクロリド樹脂(Chloro trityl chloride resin;CTL resin,Nova biochem[0064]Cat No. 01−64−0021)700mgを反応容器に入れ、メチレンクロリド(MC)10mlを加えて3分間撹拌した。溶液を除去し、ジメチルホルムアミド(DMF)10mlを入れて3分間撹拌した後、再び溶媒を除去した。反応器に10mlのジクロロメタン溶液を入れ、Fmoc−Cys(trt)−OH(Bachem、Swiss)200mmole及びジイソプロピルエチルアミン(DIEA)400mmoleを入れた後、撹拌してよく溶かし、1時間の間撹拌しながら反応させた。反応後、洗浄してメタノールとDIEA(2:1)をDCM(dichloromethane)に溶かし、10分間反応させて過量のDCM/DMF(1:1)で洗浄した。溶液を除去し、ジメチルホルムアミド(DMF)を10ml入れて3分間撹拌した後、再び溶媒を除去した。脱保護溶液(20%のピペリジン/DMF)10mlを反応容器に入れ、10分間常温で撹拌した後、溶液を除去した。同量の脱保護溶液を入れて再び10分間反応を維持した後、溶液を除去してそれぞれ3分ずつDMFで2回、MCで1回、DMFで1回洗浄してCys(trt)−CTL樹脂を製造した。
前記実施例<1−1−1>と同様の方法を用いて配列番号1のペプチド(Glu−Leu−Ile−Glu−His−Gly−Gly−Gly−Arg−Pro−Ala−Asp:ELIEHGGGRPAD)及び配列番号2のペプチド(Ac−Tyr−Lys−Ser−Lys−Lys−Gly−Gly−Trp−Thr−His:Ac−YKSKKGGWTH)を合成した。
ペプチド反応器にペプチジル樹脂(1mmol)とN,N’−ジイソプロピルエチルアミン(DIPEA)3.9g(3mmol、3.0equiv.)を1−メチル−2−ピロリジノン(NMP)10mLに溶かした後、無水コハク酸200mg(2mmol、2. 0equiv. )を投入して常温で2時間反応した。溶媒をろ過して除去し、新たなNMP(5mL X 2)を用いて洗浄することでペプチジル樹脂−コハク酸結合体を収得した。1−ヒドロキシベンゾトリアゾール(HOBt)270mg(0.2mmol、2.0equiv.)とN,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェート(HBTU)759mg(0.2mmol、2.0equiv.)をジメチルスルホキシド(DMSO)10mLに溶かして30分間反応した。N,N−ジイソプロピルエチルアミン(DIPEA)388mg(0.3mmol、3equiv.)、ミノキシジル類似体(analogue)41.8mg(0.2mM)及びペプチジル樹脂−コハク酸結合体(0.1mmol)を添加して常温で72時間の間反応し、ろ過して反応されたペプチジル樹脂を収得した。収得された樹脂を、切断溶液(cleavage solution)を用いて常温で2時間反応することで樹脂及び保護基を除去し、ジエチルエーテル10mL(10mmol)を用いて結晶化することでミノキシジルハイブリッドペプチドを収得した。
前記実施例<1−1>で製造されたミノキシジル−CG−ノッキン、ミノキシジル−CG−ケラミン2、ミノキシジル−CG−WINTをそれぞれ10mg/mlの濃度でDWに溶解させた。対照群としては、ミノキシジルを用いた。
実施例1で合成された本発明の化合物の機能を確認するため、HUVECに本発明の化合物を処理して増殖の程度を確認した。HUVECを96ウェルプレートに3000個ずつ入れ、24時間の間CO2培養器で培養した。24時間後に無血清のDMEM培地に変更し、実施例1で合成された本発明の化合物3種とミノキシジルをそれぞれ0.5uM、5uM、50uMの濃度で細胞に処理した後、72時間の間培養した。培養が完了した後、培養上澄み液を除去し、エタノールを用いて細胞を固定した後、PBS(phosphate buffer saline)で3回洗浄した。洗浄溶液を除去した後、比色SRB溶液で処理し、1%の酢酸で十分洗浄した後、顕微鏡で細胞を観察して生存細胞の状態を観察し、染色された細胞に10mMのトリス塩基(pH 10.5)溶液を加えてSRBを溶出させた後、560nm波長の紫外線で吸光度を測定して細胞の生存状態を測定した。
96ウェルプレートにHHDPCを各ウェル当り3000細胞ずつ入れ、24時間の間CO2培養器で培養した。無血清のDMEM培地に変更した後、本発明の化合物3種とミノキシジルをそれぞれ0.5uM、5uM、50uMの濃度で処理し、72時間の間培養した。培養が完了した後、前記実施例<2−1>の方法と同様の方法で細胞を染色してSRBを溶出し、細胞増殖の程度を数値化した。
VEGFは血管の生成及び拡張の機能において役割を示し、TGFβ1は脱毛に影響を与えるため、本発明の化合物処理時のVEGFとTGFβ1の発現の程度を確認した。
VEGFの発現はHUVECを用い、TGFβ1の発現は毛包の毛乳頭真皮細胞(Hair follicle dermal papilla cell)を用いた。6ウェルプレートに2つの細胞をそれぞれ各ウェル当り1×105細胞ずつ入れた。24時間の間CO2培養器で培養した後、無血清のDMEM培地に変更し、本発明の化合物3種とミノキシジルを5uM、50uMの濃度で細胞に処理した後、24時間の間培養した。培養が完了した細胞を回収し、RNA抽出キットを用いてRNAを抽出した後、RT−PCRしてVEGFとTGFβ1の発現の程度を確認した。RT−PCR時に用いたプライマーは表2に示した。
6ウェルプレートにHUVECを各ウェル当り1×105細胞ずつ入れた。24時間の間CO2培養器で培養した。無血清のDMEM培地に変更し、本発明の化合物3種とミノキシジルを5uM、50uMの濃度で細胞に処理した後、24時間の間培養した。タンパク質抽出キットを用いてタンパク質を抽出した後、ウエスタンブロットを実施した。12%のSDS−PAGEを製造した後、製造されたSDS−PAGEに15ugのタンパク質をローディングし、PVDFメンブレンに転写した。常温で1時間の間、5%の脱脂粉乳溶液でブロッキングした。1/3000の濃度で2時間の間、常温で1次抗体(anti−VEGF antibody、anti−alpha tubulin antibody)をつけた。PBSTで10分間3回洗浄し、1/5000の濃度で1時間の間、常温で2次抗体をつけた。BSTで15分間3回洗浄した後、検出した。
24ウェルプレートにマトリゲルを200ulずつ添加し、1時間培養した。マトリゲルにHUVECを1×105細胞ずつ入れた。細胞が播種されたマトリゲルに、本発明の化合物3種とミノキシジルをそれぞれ5uM、50uMの濃度で処理した。陽性対照群として用いたVEGFは、50nM、100nMの濃度で処理した。6時間後、顕微鏡を介してHUVECの血管形成の程度を観察した。
6ウェルプレートに毛包真皮乳頭細胞(Hair follicle dermal papilla cell)を各ウェル当り1×105細胞ずつ入れた。24時間の間、CO2培養器で培養した。無血清のDMEM培地に変更し、ミノキシジル、ミノキシジル−WINT、WINTを5uM、50uMの濃度で細胞に処理した後、24時間の間培養した。タンパク質抽出キットを用いてタンパク質を抽出(核/細胞質タンパク質をそれぞれ抽出)した。1次抗体として抗−βカテニン抗体、抗−HDAC抗体、抗アルファチューブリン抗体を用いたこと以外には、実施例<3−2>の方法と同様にウエスタンブロットを実施した。
本発明のミノキシジル−ノッキンが毛髪損失の主要因子であるBMP信号経路を阻害するのか否かを、phospho−Smad1/5/8活性化(細胞質から核内への移動)阻害で確認した。実施例5の方法と同様にして、BMP2の存在下でミノキシジル−WINTの代りにミノキシジル−ノッキンを処理し、1次抗体は、抗−P−Smad1/5/8抗体、抗−HDAC1抗体を用いたことだけ異なるようにして実験を進めた。
7週齢のC57BL雄マウス6匹に本発明のミノキシジル−ノッキンを塗って毛髪生長の程度を確認した。7週齢のC57BL/6マウスの背中の毛を除毛クリームを用いて全て除毛した。PBSにミノキシジル及びミノキシジル−ノッキンをそれぞれ100ug/mlの濃度で添加して試料を製造した。毎日、一日に一度ずつ、マウスの背中の皮膚にくまなく塗った。マウスの背中の皮膚の毛が育つのかを観察した後、背中の皮膚の色が黒く変わる時点から写真撮影して観察した。組織学検査のためにマウスを屠殺し、マウスの背中の皮膚を採取して4%のPFAに固定した後、パラフィンで包理した。包理されたブロックを4umにセクションしてH&E染色した後、毛包を観察した。
剤形例1:柔軟化粧水
前記実施例<1−2>で製造された本発明の化合物を含み、下記表3の組成でなる柔軟化粧水を一般的な化粧水の製造方法によって製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記表4の組成でなる栄養クリームを一般的な栄養クリームの製造方法によって製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記表5の組成でなる栄養化粧水を一般的な化粧水の製造方法によって製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記表6の組成でなるエッセンスを一般的なエッセンスの製造方法によって製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記表7の組成でなるヘアセラムを一般的なヘアセラムの製造方法によって製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記表8の組成でなるヘアトナーを一般的なヘアトナーの製造方法によって製造した。
Claims (16)
- ミノキシジルとペプチドが化学的に結合された構造を有する化合物。
- 前記ペプチドは、2から30個のアミノ酸配列でなる請求項1に記載の化合物。
- 前記ペプチドは、8から15個のアミノ酸配列でなる請求項2に記載の化合物。
- 前記ペプチドは、水溶性ペプチドである請求項1に記載の化合物。
- 前記水溶性ペプチドは、親水性側鎖を有するアミノ酸の比率が50%以上である請求項4に記載の化合物。
- 前記水溶性ペプチドは、親水性側鎖を有するアミノ酸の比率が70%以上である請求項5に記載の化合物。
- 前記水溶性ペプチドは、親水性側鎖を有するアミノ酸の比率が90%以上である請求項6に記載の化合物。
- 前記親水性側鎖を有するアミノ酸は、アルギニン(Arg)、ヒスチジン(His)、リシン(Lys)、アスパラギン酸(Asp)、グルタミン酸(Glu)、セリン(Ser)、スレオニン(Thr)、アスパラギン(Asn)、グルタミン(Gln)、システイン(Cys)、セレノシステイン(Sec)、グリシン(Gly)及びプロリン(Pro)からなる群より選択される請求項5に記載の化合物。
- 前記水溶性ペプチドは、疎水性側鎖を有するアミノ酸が5個以下である請求項4に記載の化合物。
- 前記水溶性ペプチドは、疎水性側鎖を有するアミノ酸が3個以下である請求項9に記載の化合物。
- 前記疎水性側鎖を有するアミノ酸は、アラニン(Ala)、バリン(Val)、イソロイシン(Ile)、ロイシン(Leu)、メチオニン(Met)、フェニルアラニン(Phe)、チロシン(Tyr)及びトリプトファン(Trp)からなる群より選択される請求項9に記載の化合物。
- 前記ペプチドは、配列番号1のアミノ酸配列でなるノッキンペプチド、配列番号2のアミノ酸配列でなるケラミン2ペプチド、及び配列番号3のアミノ酸配列でなるWINTペプチドからなる群より選択される請求項1に記載の化合物。
- 請求項1から請求項12のいずれか一項に記載の化合物を含有する脱毛防止又は発毛促進用薬学的組成物。
- 請求項1から請求項12のいずれか一項に記載の化合物を含有する脱毛防止又は発毛促進用化粧料組成物。
- 柔軟化粧水、栄養化粧水、栄養クリーム、マッサージクリーム、エッセンス、アイクリーム、クレンジングクリーム、クレンジングフォーム、クレンジングウォーター、パック、スプレー、パウダー、ヘアトニック、ヘアクリーム、ヘアローション、ヘアシャンプー、ヘアリンス、ヘアコンディショナー、ヘアスプレー、ヘアエアロゾル、ポマード、ゾルゲル、エマルジョン、オイル、ワックス及びエアロゾルからなる群より選択される剤形を有する請求項14に記載の化粧料組成物。
- 請求項1から請求項12のいずれか一項に記載の化合物を、脱毛が発生した個体の患部に経皮投与する段階;を含む脱毛防止又は発毛促進のための方法。
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KR102221365B1 (ko) * | 2019-05-07 | 2021-03-02 | (주)케어젠 | 트롤록스-펩타이드 결합체 및 그의 용도 |
CN110755286A (zh) * | 2019-11-18 | 2020-02-07 | 童婧 | 一种有助于生发的发际线填充组合物 |
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KR101948238B1 (ko) | 2019-02-14 |
CN109715217B (zh) | 2022-07-29 |
JP2021080273A (ja) | 2021-05-27 |
CA3034066C (en) | 2021-02-16 |
MY193527A (en) | 2022-10-18 |
ES2933848T3 (es) | 2023-02-14 |
EA201990526A1 (ru) | 2019-07-31 |
WO2018034453A1 (ko) | 2018-02-22 |
EP3501545A1 (en) | 2019-06-26 |
EP3501545A4 (en) | 2019-07-17 |
US11617796B2 (en) | 2023-04-04 |
AU2017313589B2 (en) | 2020-01-30 |
MX2019001921A (es) | 2019-07-08 |
US20190192677A1 (en) | 2019-06-27 |
KR20180020789A (ko) | 2018-02-28 |
EA038745B1 (ru) | 2021-10-13 |
AU2017313589A1 (en) | 2019-03-07 |
CA3034066A1 (en) | 2018-02-22 |
CL2019000429A1 (es) | 2019-04-26 |
ZA201901534B (en) | 2022-05-25 |
BR112019003077A2 (pt) | 2019-07-16 |
CN109715217A (zh) | 2019-05-03 |
EP3501545B1 (en) | 2022-10-26 |
JP7050052B2 (ja) | 2022-04-07 |
PH12019500345A1 (en) | 2019-12-16 |
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