JP2019504087A - ラパグルチン(rapaglutins)、glutの新規阻害剤及びその使用 - Google Patents
ラパグルチン(rapaglutins)、glutの新規阻害剤及びその使用 Download PDFInfo
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Abstract
Description
本発明は、国立衛生研究所(National Institutes of Health)の助成金 DP1CA174428 に基づく政府の支援によってなされた。米国政府は本発明に一定の権利を有する。
本発明は、細胞増殖及び T 細胞活性化を阻害するラパフシン化合物の独創性に富む発見に基づく。
試薬と条件:
(a) Fmoc-AA-OH、HATU、DIPEA、DMF、室温、2 時間;
(b) 20 % ピペリジン、DMF、室温、30 分;
(c) HATU、DIPEA、DMF、室温、2時間;
(d) ホベイダ‐グラブス触媒第2 世代 (30 mol%)、1,2-ジクロロエタン、電子レンジで 140 ℃、30 分
試薬と条件:
(a) Fmoc-AA-OH、HATU、DIPEA、DMF、室温、2 時間;
(b) 20 % ピペリジン、DMF、室温、30 分;
(c) HATU、DIPEA、DMF、室温、2 時間;
(d) ホベイダ‐グラブス触媒第2 世代 (30 mol%)、1,2-ジクロロエタン、電子レンジで 140 ℃、30 分
本発明は、細胞増殖の新規阻害剤の同定に基づく。
ヒト非小細胞肺がん(NSCLC)細胞株 A549 でのアラマー・ブルー細胞生存率アッセイを用いて、45,000 化合物及び 3000 プールのラパフシン・ライブラリーをスクリーニングした。化合物あたり 400 nM 又は 15 化合物のラパフシンのプールあたり 3 μM の最終濃度で、我々は A549 の有意な阻害を示した 50 以上のヒットを得た(図9)。ヒットの内、最も強力なプール 10 個を選択し、各プール中の個々の化合物それぞれを合成し、その後、それらのプール由来の各ラパフシンについて再試験を行った。幾つかの強力なラパフシン・ヒットが、A549 の細胞増殖を阻害するとして発見された。最も強力なラパフシン・ヒットを同定するために、最初のセットの活性化合物を、更に続けて用量依存的な解析に供した。2 つの最も強力なラパフシン A18 及び E11 の構造を図1aに示す。それぞれを実験規模で再合成し、シリカ・ゲル・クロマトグラフィーで精製した後、HPLC精製し、一連の詳細な構造決定に供した(スキーム I 及び II;図10から14)。
Claims (17)
- 被験体におけるがんを治療する方法であって、以下:
- 前記化合物が式 A18 又は E11 である、請求項1に記載の方法。
- 請求項1に記載の取り出した化合物。
- 合成スキーム I 又は II を含む、請求項3又は17に記載の化合物を合成する方法。
- 前記がんが、消化/胃腸管がん(alimentary/gastrointestinal tract cancer)、肝臓がん、皮膚がん、乳がん、膵臓がん、卵巣がん、前立腺がん、リンパ腫、白血病、腎臓がん(kidney cancer)、肺がん、筋肉がん、骨がん、膀胱がん、脳がん、眼又は眼球がん、直腸がん、結腸がん、子宮頸がん、膀胱がん、口腔がん、良性及び悪性腫瘍、胃がん、子宮体部(corpus uteri)がん、精巣がん、腎臓がん(renal cancer)、咽喉がん(throat cancer)、急性リンパ球性白血病、急性骨髄性白血病、ユーイング肉腫(Ewing's Sarcoma)、カポジ肉腫(Kaposi's Sarcoma)、基底細胞がん及び扁平上皮がん、小細胞肺がん、絨毛がん(choriocarcinoma)、横紋筋肉腫(rhabdomyosarcoma)、血管肉腫(angiosarcoma)、血管内皮腫(hemangioendothelioma)、ウィルムス腫瘍(Wilms Tumor)、神経芽細胞腫、口腔/咽頭がん(mouth/pharynx cancer)、食道がん(esophageal cancer)、咽頭がん(larynx cancer)、神経線維腫症(neurofibromatosis)、結節性硬化症、血管腫及びリンパ管形成からなる群から選択される、請求項1に記載の方法。
- 前記がんが転移性がんである、請求項5に記載の方法。
- 前記化合物を静脈投与する、請求項1に記載の方法。
- 化学療法化合物又は以下:
- 請求項3又は17に記載の化合物を含む、医薬組成物。
- 臓器移植を受けている被験体における危険性のある臓器拒絶を治療する方法であって、前記被験体に有効な量の請求項1に記載の化合物を投与することを含み、それにより危険性のある臓器拒絶を治療する方法。
- 前記化合物が、式 A18 又は E11 である、請求項10に記載の方法。
- 前記化合物を静脈投与する、請求項10に記載の方法。
- 被験体における自己免疫疾患を治療する方法であって、前記被験体に有効な量の請求項1に記載の化合物を投与することを含み、それにより自己免疫疾患を治療する方法。
- 前記化合物が、式 A18 又は E11 である、請求項13に記載の方法。
- 前記化合物を静脈投与する、請求項13に記載の方法。
- 前記自己免疫疾患が、急性播種性脳脊髄炎(ADEM)、アジソン病(Addison's disease)、強直性脊椎炎、抗リン脂質抗体症候群、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫内耳疾患、自己免疫リンパ増殖症候群(ALPS)、自己免疫性多内分泌腺/多腺性症候群(Autoimmune polyendocrine/polyglandular syndrome)、自己免疫性血小板減少性紫斑病、バロー病(Balo disease)、ベーチェット病(Behcet disease)、水疱性類天疱瘡、心筋症、セリアック・スプルー疱疹状皮膚炎(Celiac sprue-dermatitis herpetiformis)、慢性疲労免疫不全症候群(CFIDS)、慢性炎症性脱髄性ニューロパチー、瘢痕性類天疱瘡(Cicatricial pemphigoid) 、セリアック病、寒冷凝集素症(Cold agglutinin disease)、CREST 症候群、クローン病(Crohn’s disease)、嚢胞性線維症、デゴス病(Degos disease)、皮膚筋炎、糖尿病(I型又は若年発症)、早期発症型認知症、湿疹、エンドトキシン・ショック、本態性混合型クリオグロブリン血症(Essential mixed cryoglobulinemia)、家族性地中海熱、線維筋痛症、線維筋炎、グッドパスチャー症候群(Goodpasture's syndrome)、グレーブス病(Graves' disease)、ギラン・バレー症候群(Guillain-Barre syndrome (GBS))、橋本甲状腺炎、化膿性汗腺炎(Hidradenitis suppurativa)、特発性肺線維症、特発性血小板減少性紫斑病、IgA 腎症、ランバート・イートン筋無力症候群(Lambert-Eaton Myasthenic Syndrome)、白血病、扁平苔癬、メニエール病(Meniere disease)、混合性結合組織病(Mixed connective tissue disease)、多発性硬化症、多相性散在性脳脊髄炎(Multiphasic disseminated encephalomyelitis)、重症筋無力症、視神経脊髄炎(Neuromyelitis Optica)、腫瘍随伴症候群(Paraneoplastic Syndromes)、天疱瘡、尋常性天疱瘡、悪性貧血 、結節性多発動脈炎、多発性軟骨炎、リウマチ性多発筋痛、多発性筋炎、原発性無ガンマグロブリン血症、原発性胆汁性肝硬変、プラーク乾癬(Plaque Psoriasis)、乾癬性関節炎、レイノー現象(Raynaud phenomenon)、ライター症候群(Reiter syndrome)、血管形成術後の再狭窄、リウマチ熱、関節リウマチ、リウマチ様乾癬(Rheumatoid psoriasis)、サルコイドーシス、強皮症、敗血症、セザリー病(Sezary’s disease)、シェーグレン症候群(Sjogren's syndrome)、スティッフ−パーソン症候群(Stiff-person syndrome)、全身性エリテマトーデス(SLE)を含むループス、高安動脈炎、側頭動脈炎(「巨細胞性動脈炎」としても知られている)、移植又は同種移植片拒絶、潰瘍性大腸炎、ブドウ膜炎、血管炎、白斑、移植片対宿主病、膿疱性乾癬、及びウェゲナー(Wegener)肉芽腫症(現在、多発血管炎性肉芽腫症(GPA)と名付けられている)、炎症性腸疾患、急性壊死性出血性白質脳炎(Acute necrotizing hemorrhagic leukoencephalitis)、無ガンマグロブリン血症、円形脱毛症、アミロイドーシス、抗GBM/抗 TBM 腎炎、抗リン脂質症候群(APS)、自己免疫性血管性浮腫(Autoimmune angioedema)、自己免疫性無形成性貧血(Autoimmune aplastic anemia,)、自己免疫性自律神経障害、自己免疫性高脂血症、自己免疫性免疫不全症、自己免疫性内耳疾患(AIED)、自己免疫性心筋炎、自己免疫性卵巣炎、自己免疫性膵炎、自己免疫性網膜症、自己免疫性甲状腺疾患、自己免疫性蕁麻疹、軸索及び神経性ニューロパチー(Axonal & neuronal neuropathies)、キャッスルマン病(Castleman disease)、セリアック病、シャーガス病(Chagas disease)、慢性疲労症候群、慢性炎症性脱髄性多発神経炎(Chronic inflammatory demyelinating polyneuropathy (CIDP))、慢性再発性多発性骨髄炎(Chronic recurrent multifocal ostomyelitis (CRMO))、チャーグ−ストラウス症候群(Churg-Strauss syndrome)、瘢痕性類天疱瘡/良性粘膜類天疱瘡、コガン症候群(Cogans syndrome )、先天性心臓ブロック(Congenital heart block)、コクサッキー心筋炎(Coxsackie myocarditis)、CREST 病(CREST disease )、脱髄性ニューロパチー、疱疹状皮膚炎(Dermatitis herpetiformis)、デビック病(視神経脊髄炎)(Devic’s disease)、円盤状ループス、ドレスラー症候群(Dressler’s syndrome)、子宮内膜症、好酸球性食道炎、好酸球性筋膜炎、結節性紅斑、実験的アレルギー性脳脊髄炎、エバンス症候群(Evans syndrome)、線維化性肺胞炎、巨細胞性動脈炎(側頭動脈炎)、巨細胞性心筋炎、糸球体腎炎、多発血管炎性肉芽腫症(GPA)(以前はウェゲナー肉芽腫症と呼ばれていた)、橋本脳炎(Hashimoto’s encephalitis)、橋本甲状腺炎、溶血性貧血、ヘノッホ−シェーンライン紫斑病(Henoch-Schonlein purpura)、妊娠性疱疹、低ガンマグロブリン血症、特発性血小板減少性紫斑病(ITP)、IgG4関連硬化性疾患(IgG4-related sclerosing disease)、免疫調節性リポタンパク質、封入体筋炎、間質性膀胱炎、若年性関節炎、若年性糖尿病(I 型糖尿病)、若年性筋炎、川崎症候群(Kawasaki syndrome)、ランバート−イートン症候群(Lambert-Eaton Syndrome)、白血球破砕性血管炎(Leukocytoclastic vasculitis)、硬化性苔癬、木質性結膜炎、線状 IgA 病(Linear IgA disease (LAD))、ループス(SLE)、ライム病(Lyme disease)、慢性(chronic) 、顕微鏡的多発血管炎、モーレン潰瘍(Mooren’s ulcer)、ムッハ−ハーベルマン病(Mucha-Habermann disease)、筋炎、ナルコレプシー、好中球減少症、眼部瘢痕性類天疱瘡(Ocular cicatricial pemphigoid)、視神経炎、パリンドローム・リウマチ、PANDAS(小児自己免疫性溶連菌関連性精神神経障害(Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus))、傍腫瘍性小脳変性症(Paraneoplastic cerebellar degeneration)、発作性夜間ヘモグロビン尿症(PNH)、パリー・ロンベルグ症候群(Parry Romberg syndrome)、パーソネイジ−ターナー症候群(Parsonnage-Turner syndrome)、扁平部炎(Pars planitis (peripheral uveitis))、天疱瘡、末梢神経障害、静脈周囲脳脊髄炎(Perivenous encephalomyelitis)、POEMS 症候群、I, II, & III 型多腺性自己免疫症候群、心筋梗塞後症候群、心膜切開後症候群、プロゲステロン皮膚炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、乾癬、乾癬性関節炎、特発性肺線維症、壊疽性膿皮症、赤芽球癆(Pure red cell aplasia)、反応性関節炎、反射交感神経ジストロフィー(Reflex sympathetic dystrophy)、再発性多発軟骨炎、むずむず脚症候群(Restless legs syndrome)、後腹膜線維症、リウマチ熱、シュミット症候群(Schmidt syndrome)、強膜炎、精子 & 精巣の自己免疫(Sperm & testicular autoimmunity)、亜急性細菌性心内膜炎(SBE)、スザック症候群(Susac’s syndrome)、交感性眼炎、血小板減少性紫斑病(TTP)、トロサ−ハント症候群(Tolosa-Hunt syndrome)、横断性脊髄炎、I 型糖尿病、未分化型結合組織病(UCTD)及び水疱性皮膚症からなる群から選択される、請求項13に記載の方法。
- 以下の構造を有する化合物:
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US11066416B2 (en) | 2016-02-04 | 2021-07-20 | The Johns Hopkins University | Rapafucin derivative compounds and methods of use thereof |
EP3411046A4 (en) | 2016-02-04 | 2019-11-27 | The Johns Hopkins University | RAPAGLUTINES, NOVEL GLUT INHIBITORS AND USES THEREOF |
MX2018009407A (es) | 2016-02-04 | 2018-11-09 | Univ Johns Hopkins | Rapadocinas, inhibidores de transportador 1 de nucleósido equilibrador y sus usos de los mismos. |
TW202126323A (zh) * | 2019-10-01 | 2021-07-16 | 約翰斯赫普金斯大學 | 雷帕弗辛(Rapafucin)衍生化合物及其使用方法 |
CN112294792B (zh) * | 2020-09-22 | 2021-10-22 | 厦门市中医院 | 化合物wzb117在制备治疗和/或预防肝损伤药物中的用途 |
CN115364224B (zh) * | 2022-08-25 | 2024-02-02 | 杭州天玑济世生物科技有限公司 | Glut1抑制剂作为线粒体自噬诱导剂的用途 |
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