JPWO2020138067A1 - ピラジン誘導体と細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物とを組み合わせてなるrnaウイルス感染症治療剤 - Google Patents
ピラジン誘導体と細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物とを組み合わせてなるrnaウイルス感染症治療剤 Download PDFInfo
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- JPWO2020138067A1 JPWO2020138067A1 JP2020563301A JP2020563301A JPWO2020138067A1 JP WO2020138067 A1 JPWO2020138067 A1 JP WO2020138067A1 JP 2020563301 A JP2020563301 A JP 2020563301A JP 2020563301 A JP2020563301 A JP 2020563301A JP WO2020138067 A1 JPWO2020138067 A1 JP WO2020138067A1
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- rna virus
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- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
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Abstract
Description
[1]
一般式[1]
[2]
R1が水素原子、R2がフッ素原子又は水素原子、及びR3が水素原子である[1]に記載の治療剤。
[3]
R1が水素原子、R2がフッ素原子、及びR3が水素原子である[2]に記載の治療剤。
[4]
細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物が、葉酸拮抗剤、チオプリン系代謝拮抗剤、チアゾフリン、アルキル化剤およびキサンチン誘導体からなる群から選ばれる一種以上の化合物である、[1]から[3]いずれか一に記載の治療剤。
[5]
葉酸拮抗剤がメトトレキサート又はプララトレキサートであり、チオプリン系代謝拮抗剤が一般式[2]
[6]
チオプリン系代謝拮抗剤が、6−メルカプトプリン、アザチオプリン又は6−チオグアニンである[5]に記載の治療剤。
[7]
一つ以上の他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤をさらに組み合わせてなる、[1]から[6]いずれか一に記載の治療剤。
[8]
他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤がリバビリンである、[7]に記載の治療剤。
[9]
一般式[1]
[10]
細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物と併用される、一般式[1]
[11]
R1が水素原子、R2がフッ素原子又は水素原子、及びR3が水素原子である[10]に記載の治療剤。
[12]
R1が水素原子、R2がフッ素原子、及びR3が水素原子である[11]に記載の治療剤。
[13]
細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物が、葉酸拮抗剤、チオプリン系代謝拮抗剤、チアゾフリン、アルキル化剤およびキサンチン誘導体からなる群から選ばれる一種以上の化合物である、[10]から[12]いずれか一に記載の治療剤。
[14]
葉酸拮抗剤がメトトレキサート又はプララトレキサートであり、チオプリン系代謝拮抗剤が一般式[2]
[15]
チオプリン系代謝拮抗剤が、6−メルカプトプリン、アザチオプリン又は6−チオグアニンである[14]に記載の治療剤。
[16]
葉酸拮抗剤、チオプリン系代謝拮抗剤、チアゾフリン、アルキル化剤およびキサンチン誘導体からなる群から選ばれる一種以上の化合物と併用される、一般式[1]
[17]
一つ以上の他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤とさらに併用される、[10]から[15]いずれか一に記載の治療剤。
[18]
他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤がリバビリンである、[17]に記載の治療剤。
[A]
一般式[1]
[B]
RNAウイルス感染症治療薬を製造するための、一般式[1]
[C]
RNAウイルス感染症の治療において使用するための、一般式[1]
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子及びヨウ素原子を意味する。C1−6アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、イソブチル、tert−ブチル、ペンチル、イソペンチル、2−メチルブチル、2−ペンチル、3−ペンチル及びヘキシル基などの直鎖状又は分枝鎖状のC1−6アルキル基を意味する。
ピラジン誘導体と代謝拮抗剤を組み合わせた時のRNAウイルスに対する効果を、ウイルスのRNA依存性RNAポリメラーゼ(RdRp)複合体のレプリコン活性により調べた。レプリコン活性評価のため、公知の方法(Neumann, G.ら、J. Virol. 74: 547−551 (2000))を参考に、細胞を用いたレポーターアッセイ系を構築した。このアッセイ系では、レポータータンパク質であるルシフェラーゼ(Luc)の活性により、レプリコン活性を評価した。
(1−1)野生型ウイルスタンパク質遺伝子のクローニング
上記公知文献に記載の方法で、ウイルスタンパク質PA、PB1、PB2、NPをコードする遺伝子を、Influenza A/PR/8/34(H1N1)株からRT−PCR法により増幅し、pcDNA3.1ベクターにクローニングした。得られたpcDNA3.1/PR8_PAプラスミドDNA、pcDNA3.1/PR8_PB1プラスミドDNA、pcDNA3.1/PR8_PB2プラスミドDNA及びpcDNA3.1/PR8_NPプラスミドDNAは、それぞれ野生型PA DNA、野生型PB1 DNA、野生型PB2 DNA及び野生型NP DNAと命名した。
次に、レポーター遺伝子を含むプラスミドDNAを作製した。具体的には、5´末端から3´末端にかけて、ヒト由来ポリメラーゼIプロモーターをコードする領域(Jones, M. H.ら、Proc. Natl. Acad. Sci. USA 85: 669−673 (1988))、Influenza A/PR/8/34(H1N1)株のNTRで挟まれたLuc遺伝子、マウス由来ポリメラーゼIターミネーターをコードする領域(Grummt, I.ら、Cell 45: 837−846 (1986))でつなげたDNAを作製し、pcDNA3.1ベクターにクローニングし、レポータープラスミドpcDNA3.1/polI_NTR_RhLucを得た。
(1−3−1)293T細胞の培養
細胞は、SV40 large T抗原を発現しているヒト胎児腎細胞293T細胞(以下、293T細胞とする)を用いた。10%ウシ胎児血清添加DMEM培地中、5%二酸化炭素条件下、37℃で継代培養されている293T細胞を、エチレンジアミン四酢酸トリプシン法によって剥離し、2.4×107cells/225cm2フラスコとなるように播種した。その後、5%二酸化炭素条件下、37℃で一夜培養し、単層の293T細胞を得た。
Opti−MEM(サーモフィッシャーサイエンティフィック社製)3mLに対し野生型PA DNAを0.96μg、野生型PB1 DNAを9.6μg、野生型PB2 DNAを9.6μg、野生型NP DNAを9.6μg及び2種のレポータープラスミドpcDNA3.1/polI_NTR_RhLucを9.6μg、(DNA導入の成否を確認するため)pGL4.54(プロメガ社製、#E5061)を9.6μgとなるように調整し、Lipofectamine LTX Reagent with PLUS Reagent(サーモフィッシャーサイエンティフィック社製)に添付のPLUS Reagent 49μLを添加した。またOpti−MEM 2.9mLにLipofectamine LTX Reagent 0.23mLを添加し5分間放置した。その後、二液を体積比で1対1となるように混ぜ合わせ、室温で15分放置した。上記混合液を、6mL/225cm2フラスコとなるように293T細胞の培養フラスコへ添加し、約6時間放置して、インフルエンザウイルスのRdRp、NP及びレポータープラスミドを細胞に導入した。
(2−1)細胞への薬剤添加及び培養
(B)代謝拮抗剤単剤(最終濃度:10μM〜0.08μM,10μMから公比5で5段階希釈)及び0.1%DMSO含有培地
(C)T−705(最終濃度:10μM)、代謝拮抗剤(最終濃度:10μM〜0.08μM,10μMから公比5で5段階希釈)及び0.1%DMSO含有培地
(D)0.1%DMSO含有培地
(A)〜(D)のいずれも、10%ウシ胎児血清添加DMEM培地で希釈及び混合した。
Luc活性の測定には、Dual−Glo Luciferase Assay System(プロメガ社製)を用いた。約20時間の培養後に、該Systemに添付のDual−Glo Reagentを20μL/ウェル添加し、10分以上室温で撹拌させ、細胞を溶解した。その後、マイクロプレートリーダー(パーキンエルマー社製、2104 EnVision)にて発光強度を測定した。続いて、該Systemに添付のStop & Glo Reagentを20μL/ウェル添加し、10分以上室温で攪拌後、マイクロプレートリーダー(同上)にて発光強度を測定した。例数は1で実施した。以下に示す式から、レプリコン反応率及びレプリコン阻害率を算出した。
(2−1)と同様に、以下(E)〜(H)の試験液を用いて、細胞への薬剤添加と培養を行った。(2−2)と同様に、レプリコン阻害活性を評価した。
(F)代謝拮抗剤単剤(最終濃度:0.03μM〜200μM,200μMから公比3で10段階希釈、又は20μMから公比2で10段階希釈)及び0.1%DMSO含有培地
(G)T−705、(最終濃度:1.4μM〜1000μM,1000μMから公比3で8段階希釈)代謝拮抗剤(最終濃度:0.03μM〜200μM,200μMから公比3で10段階希釈、又は20μMから公比2で10段階希釈)及び0.1%DMSO含有培地
(H)0.1%DMSO含有培地
ピラジン誘導体と代謝拮抗剤の併用効果について、ウイルスの細胞感染モデルで、さらに試験を行った。
培養液10%ウシ胎児血清添加イーグルMEM培地中、5%二酸化炭素条件下、37℃で継代培養されているマージン−ダービー イヌ腎(Madin−Darby Caine Kidney)(以下、MDCKとする)細胞をエチレンジアミン四酢酸トリプシン法によって剥離し、同培地で100μLに2×104個の細胞を含むように調製した懸濁液を96ウェルプレートに播種した。5%二酸化炭素条件下、37℃で一夜培養し、単層となったMDCK細胞を得た。
試験培地として、カナマイシン60μg/mLを加えたイーグルMEM培地に1μg/mLとなるようL−1−トシルアミド−2−フェニルエチルクロロメチルケトン(TPCK)処理トリプシンを加えた培地を用いた。(1)で得られたMDCK細胞の培養上清を取り除き、イーグルMEM培地ですすいだ後、各ウェルに、以下(A)〜(C)を加えた。薬剤添加後、5%二酸化炭素条件下、35℃で3〜4日間培養した。
(B)試験培地の4倍濃度のTPCK処理トリプシンを含むイーグルMEM培地で4.0×103PFU/mLに調整したインフルエンザウイルス(PR/8(H1N1))液を50μL
(C)設定濃度の4倍濃度のT−705及び6−メルカプトプリンの、各設定濃度の組み合わせを含むイーグルMEM培地を50μL
T−705設定濃度(μM):0, 0.01,1,3,10,30
6−メルカプトプリン設定濃度(μM):0, 0.1,0.3,1,3,10
インフルエンザウイルスの増殖に伴って認められる細胞変性効果(CPE)を、以下の方法で判定した。
試験例2と同じインフルエンザウイルス細胞感染モデルを用いて、ピラジン誘導体と代謝拮抗剤と他のRNAウイルス感染症治療剤の併用効果について、さらに試験を行った。
T−705設定濃度(μM):0, 0.01,0.03,0.1,0.3,1,3,10,30
リバビリン設定濃度(μM):0, 0.1,0.3,1,3,10,30,100
6−メルカプトプリン設定濃度(μM):0, 10
インフルエンザ以外のウイルスの細胞感染モデルで、ブニヤウイルスであるPunta Toroウイルスを用いて試験例2と同様の試験を行った。ピラジン誘導体として、T−705を選択した。化合物として、6−メルカプトプリン、アザチオプリン、テモゾロミド、テオフィリン及びチアゾフリンを選択した。
細胞は、293T細胞を用いた。10%ウシ胎児血清添加DMEM培地中、5%二酸化炭素条件下、37℃で継代培養されている293T細胞を、エチレンジアミン四酢酸トリプシン法によって剥離し、同培地で1mLに1×105個の細胞を含むように調製した懸濁液を24ウェルプレートに播種し、5%二酸化炭素条件下、37℃で一夜培養した。
(1)で得られた293T細胞の培養上清を取り除き、イーグルMEM培地ですすいだ後、各ウェルに1.0×103PFU/mLに調整したPunta Toroウイルス液を0.1mLずつ添加し、5%二酸化炭素条件下、37℃で1時間培養した。ウイルス液を除去後、T−705単剤(最終濃度:20μM)、代謝拮抗剤(最終濃度:10μM)又はT−705単剤(最終濃度:20μM)と代謝拮抗剤(最終濃度:10μM)を混合した1%ウシ胎児血清添加イーグルMEM培地を加え、5%二酸化炭素条件下、37℃で3日間培養した。また、感染コントロールとして、薬剤を含む培地の代わりに、1%ウシ胎児血清添加イーグルMEM培地を加えた。
(3−1)Vero細胞の培養
培養液10%ウシ胎児血清添加イーグルMEM培地中、5%二酸化炭素条件下、37℃で継代培養されているサル腎Vero細胞をエチレンジアミン四酢酸トリプシン法によって剥離し、2%ウシ胎児血清添加イーグルMEM培地で100μLに2×104個の細胞を含むように調製した懸濁液を96ウェルプレートに播種した。5%二酸化炭素条件下、37℃で一夜培養し、単層となったVero細胞を得た。
(3−1)で得られたVero細胞に(2)で取得したウイルス培養液をイーグルMEM培地で公比10、5段階に希釈し、原液及び希釈液を50μLずつ添加した(n=4)。5%二酸化炭素条件下、37℃で3〜4日間培養した。
培養終了後、各ウェルに100%ホルマリン液を50μL加え、ウイルスの不活性化及び細胞固定した。2時間以上室温で静置後、0.005%メチレンブルー液を100μL/ウェルを加え1時間室温で静置した。0.005%メチレンブルー液を除去し、水で軽く洗浄した後、風乾させた。その後、各サンプルの50%感染量の対数値(LogTCID50)を以下のBohrens−Karber法の式を用いて算出した。感染コントロールに対するウイルス量低下効果をΔLogTCID50で示した。
D:全ウェル(n=4)がCPE陽性(陽性率=1)であった最高希釈倍率の常用対数
h:各ウェルのCPE陽性率 (<1の場合)
d:試料の希釈倍率の常用対数
前記の通り、ピラジン誘導体又はその塩は、細胞内でリボシルリン酸化を受ける。例えばT−705は、リボシルリン酸化により生じるT−705−4−ribofuranosyl−5−triphosphate(T−705RTP)がウイルスのRdRpタンパク質を阻害することによって抗ウイルス作用を示すことが知られている。試験例1で見られた6−メルカプトプリンによるT−705の活性増強効果は、T−705RTP量の変化によるものかどうかを確認するため、293T細胞における6―メルカプトプリン処理下でのT−705RTP量を測定した。
(1−1)細胞内T−705RTPの抽出
6ウェルプレートの各ウェルに5×105cells播種した293T細胞をvehicle(0.3%DMSO)又は様々な濃度の6−メルカプトプリン、T−705、又は両薬剤に5%二酸化炭素条件下、37℃で24時間培養した。
細胞数の測定及びLC/MS/MS分析を行い、各サンプル中のT−705RTP量を測定した。試験方法は、Matsuda S, Kasahara T. Genes Environ. 40:13.(2018)に従って実施した。T−705RTP量の変化を図1に示す。6−メルカプトプリンにより、T−705処理後の細胞内T−705RTP量が増加したことが分かった。
Claims (18)
- R1が水素原子、R2がフッ素原子又は水素原子、及びR3が水素原子である請求項1記載の治療剤。
- R1が水素原子、R2がフッ素原子、及びR3が水素原子である請求項2記載の治療剤。
- 細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物が、葉酸拮抗剤、チオプリン系代謝拮抗剤、チアゾフリン、アルキル化剤およびキサンチン誘導体からなる群から選ばれる一種以上の化合物である、請求項1から3いずれか一項に記載の治療剤。
- チオプリン系代謝拮抗剤が、6−メルカプトプリン、アザチオプリン又は6−チオグアニンである請求項5に記載の治療剤。
- 一つ以上の他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤をさらに組み合わせてなる、請求項1から6いずれか一項に記載の治療剤。
- 他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤がリバビリンである、請求項7に記載の治療剤。
- R1が水素原子、R2がフッ素原子又は水素原子、及びR3が水素原子である請求項10記載の治療剤。
- R1が水素原子、R2がフッ素原子、及びR3が水素原子である請求項11記載の治療剤。
- 細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物が、葉酸拮抗剤、チオプリン系代謝拮抗剤、チアゾフリン、アルキル化剤およびキサンチン誘導体からなる群から選ばれる一種以上の化合物である、請求項10から12いずれか一項に記載の治療剤。
- チオプリン系代謝拮抗剤が、6−メルカプトプリン、アザチオプリン又は6−チオグアニンである請求項14に記載の治療剤。
- 一つ以上の他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤とさらに併用される、請求項10から15いずれか一項に記載の治療剤。
- 他のRNAウイルス感染症治療剤又は抗RNAウイルス阻害作用を示す薬剤がリバビリンである、請求項17に記載の治療剤。
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---|
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