JP2019508397A - ラパドシン(Rapadocins)、受動拡散型ヌクレオシド輸送体1阻害剤及びその使用 - Google Patents
ラパドシン(Rapadocins)、受動拡散型ヌクレオシド輸送体1阻害剤及びその使用 Download PDFInfo
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Abstract
式 I を含む組成物を使用して、ヒト受動拡散型ヌクレオシド輸送体 1 を阻害し、アデノシン・シグナル伝達を増加させ、抗ウイルス活性の増加、抗寄生虫活性の増加、アルコール耐性の増加、疼痛の減少及び虚血、その他の症状からの保護等を含む効果を生み出す。
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。
本発明の他の態様及び利点は、以下の説明から明らかになるであろう。ラパドシンである式 I(RapADOcin として定型化され又は JW95 とも呼ぶ)は、合成大員環状低分子である。ラパドシンは、ヒト受動拡散型ヌクレオシド輸送体 1(hENT1 又は SLC29a1)を高い効力で特異的に阻害する。
ラパドシンはヌクレオシド取り込みを阻害する
ラパドシンは、2 種類の最も主要な受動拡散型ヌクレオシド輸送体の内、hENT2よりも、ヒト受動拡散型ヌクレオシド取り込み輸送体 1(hENT1)によるヌクレオシドの取り込みを、強力かつ特異的に阻害する(図1)。
表2は様々なラパドシン類縁体の効力を開示する。
ヒトと動物のモデル
ラパドシンの有効性を示すために、2 つのヒト及び動物モデルで研究を行った(図4及び5)。いくつかの生理学的条件下で、アデノシンは血液中に放出され、そこでアデノシン受容体に作用し得る。通常、このアデノシン(ADO)は ENT1 を介して迅速に再吸収される。ラパドシンの存在下では、取り込みが阻害され、ADO は、いくつかの潜在的に有益な生理学的応答をもたらす増強されたシグナル伝達を生成することができる。
前記リードの薬物動態/薬力学及び溶解性を改善するために使用することができる追加的な化合物は、以下を含む:
スキーム 1
FKBD 8を用いたラパドシンの合成経路。
薬物動態/薬力学及び溶解度を改善するために使用することができる化合物は、以下の一般構造によって表される:
以下の参考文献はそれぞれ、本明細書に援用され、その全体が本明細書に組み込まれる。
1) Passer, B. J. et al. Identification of the ENT1 Antagonists Dipyridamole and Dilazep as Amplifiers of Oncolytic Herpes Simplex Virus-1 Replication. Cancer Res. 70, 3890-3895 (2010).
2) Kose, M. & Schiedel, A. C. Nucleoside/nucleobase transporters: drug targets of the future? Future Med. Chem. 1, 303-326 (2009).
3) Melendez, R. I. & Kalivas, P. W. Last call for adenosine transporters. Nat. Neurosci. 7, 795-796 (2004).
4) Choi, D.‐S. et al. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat. Neurosci. 7, 855-861 (2004).
5) Puetz, C. et al. Nitrobenzylthioinosine compounds for relief of pain. (Google Patents, 2008). at <https://www.google.com/patents/US7358235>
6) Sawynok, J. in Adenosine 343-360 (Springer, 2013). at <http://link.springer.com/chapter/10.1007/978-1-4614- 3903-5_17>
7) Bauerle, J. D., Grenz, A., Kim, J.-H., Lee, H. T. & Eltzschig, H. K. Adenosine Generation and Signaling during Acute Kidney Injury. J. Am. Soc. Nephrol. 22, 14-20 (2011).
8) Grenz, A. et al. The Reno-Vascular A2B Adenosine Receptor Protects the Kidney from Ischemia. PLoS Med. 5, e137 (2008).
9) Grenz, A. et al. Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. J. Clin. Invest. 122, 693-710 (2012).
10)Zimmerman, M. A. et al. Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion. Hepatology 58, 1766-1778 (2013).
11)Mohamadnejad, M. et al. Adenosine inhibits chemotaxis and induces hepatocyte-specific genes in bone marrow mesenchymal stem cells. Hepatology 51(3), 963-73 (2010).
12)Wen, J. et al.Adenosine signaling: good or bad in erectile function? Arterioscler Thromn Vasc Biol 32(4), 845-50 (2012).
13)Xu, Z. et al. ENT1 inhibition attenuates epileptic seizure severity via regulation of glutamatergic neurotransmission. Neuromolecular Med. 17(1), 1-11 (2015).
14)Chen, J. eta al. Adenosine receptors as drug targets-what are the challenges? Nat Rev Drug Disc 12(4), 265-86 (2013).
15)Sachdeva, S. et al. Adenosine and its receptors as therapeutic targets: An overview. Saudi Pharmaceutical Journal 21, 245-253 (2013).
16)Griffith et al., Biochim. Bioph. Acta 1286:153-181 (1986).
17)Lu X et al., Journal of Experimental Therapeutics and Oncology 2:200-212, 2002.
18)Pennycooke M et al., Biochemical and Biophysical Research Communications 208, 951-959, 2001.
Claims (8)
- 以下の内の一つからなる群から選択される化合物:
式 I (JW95, ラパドシン)
- ヒト受動拡散型ヌクレオシド輸送体 1(ENT1)を阻害する方法であって、それを必要とする被験体に、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ENT1 を阻害する方法。
- アデノシン・シグナル伝達を増加させる方法であって、それを必要とする被験体に、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、それによりアデノシン・シグナル伝達を増加させる方法。
- アデノシン・シグナル伝達を増加させる方法であって、それを必要とする被験体に、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、請求項 1 に記載の化合物を投与することにより、抗ウイルス活性の増加、抗寄生虫活性の増加、アルコール耐性の増加、疼痛の減少及び虚血からの保護、てんかん発作の重症度の低下、勃起不全の軽減、肝機能の改善、呼吸器疾患の改善、敗血症の改善、血栓症の改善、高血圧の改善、炎症性疾患の改善、アレルギーの改善、心虚血の改善、不整脈の改善、パーキンソン病の改善、慢性心不全の改善、間接リウマチの改善、ドライアイ疾患の改善、慢性局面型乾癬(chronic plaque type psoriasis)の改善、慢性神経因性疼痛の改善及び鎌状赤血球疾患の改善からなる群から選択される 1 つ以上の効果をもたらす方法。
- 以下の構造の化合物:
- ヒト受動拡散型ヌクレオシド輸送体 1(ENT1)を阻害する方法であって、それを必要とする被験体に、有効な量の請求項 5 に記載の化合物を投与することを含み、それにより ENT1 を阻害する方法。
- アデノシン・シグナル伝達を増加させる方法であって、それを必要とする被験体に、有効な量の請求項 5 に記載の化合物を投与することを含み、それによりアデノシン・シグナル伝達を増加させる方法。
- アデノシン・シグナル伝達を増加させる方法であって、それを必要とする被験体に、有効な量の請求項 5 に記載の化合物を投与することを含み、請求項 5 に記載の化合物を投与することにより、抗ウイルス活性の増加、抗寄生虫活性の増加、アルコール耐性の増加、疼痛の減少及び虚血からの保護、てんかん発作の重症度の低下、勃起不全の軽減、肝機能の改善、呼吸器疾患の改善、敗血症の改善、血栓症の改善、高血圧の改善、炎症性疾患の改善、アレルギーの改善、心虚血の改善、不整脈の改善、パーキンソン病の改善、慢性心不全の改善、間接リウマチの改善、ドライアイ疾患の改善、慢性局面型乾癬(chronic plaque type psoriasis)の改善、慢性神経因性疼痛の改善及び鎌状赤血球疾患の改善からなる群から選択される 1 つ以上の効果をもたらす方法。
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US11066416B2 (en) | 2016-02-04 | 2021-07-20 | The Johns Hopkins University | Rapafucin derivative compounds and methods of use thereof |
MX2018009408A (es) * | 2016-02-04 | 2018-11-09 | Univ Johns Hopkins | Rapaglutinas, nuevos inhibidores de transportadores de glucosa (glut) y uso de los mismos. |
CA3013650A1 (en) * | 2016-02-04 | 2017-08-10 | The Johns Hopkins University | Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof |
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 |
AU2021253634A1 (en) * | 2020-04-07 | 2022-11-03 | iTeos Belgium SA | Macrocyclic diamine derivatives as ENT inhibitors for the treatment of cancers, and combination thereof with adenosine receptor antagonists |
WO2023059739A1 (en) * | 2021-10-06 | 2023-04-13 | iTeos Belgium SA | Macrocyclic compounds having ent1 inhibiting activity |
WO2023056910A1 (en) * | 2021-10-06 | 2023-04-13 | iTeos Belgium SA | Processes for preparing a macrocyclic compound having ent1 inhibiting activity |
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AU2017214557B2 (en) | 2022-05-19 |
EP3782636B1 (en) | 2024-05-15 |
JP7022069B2 (ja) | 2022-02-17 |
MX2021002588A (es) | 2021-04-19 |
US20200392182A1 (en) | 2020-12-17 |
CA3013650A1 (en) | 2017-08-10 |
EP3782636A1 (en) | 2021-02-24 |
ES2837484T3 (es) | 2021-06-30 |
CN113999281A (zh) | 2022-02-01 |
US20190031716A1 (en) | 2019-01-31 |
AU2017214557A1 (en) | 2018-08-16 |
EP3411032B1 (en) | 2020-09-30 |
US11555054B2 (en) | 2023-01-17 |
EP3411032A4 (en) | 2019-08-14 |
EP3411032A1 (en) | 2018-12-12 |
CN108697701A (zh) | 2018-10-23 |
MX2018009407A (es) | 2018-11-09 |
WO2017136717A1 (en) | 2017-08-10 |
US10774110B2 (en) | 2020-09-15 |
CN108697701B (zh) | 2021-10-26 |
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