阿吡莫德

**阿吡莫德**
臨床資料
其他名稱	STA-5326
法律規範狀態
法律規範	美：Investigational New Drug;
識別資訊
	IUPAC命名法 N-[(E)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine; ;
CAS號	541550-19-0
PubChem CID	10173277;
DrugBank	05611;
ChemSpider	8348782;
UNII	GFW2K84S4L;
ECHA InfoCard	100.237.985
化學資訊
化學式	C23H26N6O2
摩爾質量	418.50 g·mol−1
3D模型（JSmol（英語：JSmol））	交互式圖像;
	SMILES CC1=CC(=CC=C1)/C=N/NC2=CC(=NC(=N2)OCCC3=CC=CC=N3)N4CCOCC4;
	InChI InChI=1S/C23H26N6O2/c1-18-5-4-6-19(15-18)17-25-28-21-16-22(29-10-13-30-14-11-29)27-23(26-21)31-12-8-20-7-2-3-9-24-20/h2-7,9,15-17H,8,10-14H2,1H3,(H,26,27,28)/b25-17+; Key:HSKAZIJJKRAJAV-KOEQRZSOSA-N;

阿吡莫德（INN：apilimod；開發代號：STA-5326），或譯阿匹莫德，是一種最初被確定為可以抑制白細胞介素 IL-12和IL-23產生的藥物，並被開發用於口服治療克羅恩病和類風濕性關節炎等自身免疫性疾病，^[1]但是臨床試驗結果令人失望，而且這些藥物的開發申請也暫停了。^[2]^[3]

隨後，人們發現阿吡莫德還有另一種作用方式，即作為脂質激酶PIKfyve（英語：PIKFYVE）的抑制劑。^[4]^[5]PIKfyve產生兩種脂質，即PtdIns5P和PtdIns(3,5)P2。在體外測定中，它們的合成可被阿吡莫德（ID50 = 0.4 nM）有效地抑制。在人胚胎腎細胞中施用阿匹莫德（100 nM；60分鐘）可顯着降低PtdIns5P和PtdIns(3,5)P2的水平。^[6]

最近，阿吡莫德已被提議用作潛在的抗病毒和抗癌藥物，可用於治療非霍奇金淋巴瘤以及埃博拉病毒病、拉沙熱和COVID-19等病毒性疾病。^[7]^[8]^[9]^[10]^[11]

參考資料[編輯]

^ Billich A. Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency. IDrugs. January 2007, 10 (1): 53–9. PMID 17187316.
^ Sands BE, Jacobson EW, Sylwestrowicz T, Younes Z, Dryden G, Fedorak R, Greenbloom S. Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease. Inflammatory Bowel Diseases. July 2010, 16 (7): 1209–18. PMID 19918967. S2CID 26012456. doi:10.1002/ibd.21159 .
^ Krausz S, Boumans MJ, Gerlag DM, Lufkin J, van Kuijk AW, Bakker A, et al. Brief report: a phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis. Arthritis and Rheumatism. June 2012, 64 (6): 1750–5. PMID 22170479. doi:10.1002/art.34339.
^ Shisheva A, Sbrissa D, Ikonomov O. Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells. Molecular and Cellular Biology. 1999, 19 (1): 623–634. PMC 83920 . PMID 9858586. doi:10.1128/mcb.19.1.623 .
^ Cai X, Xu Y, Cheung AK, Tomlinson RC, Alcázar-Román A, Murphy L, et al. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chemistry & Biology. July 2013, 20 (7): 912–21. PMC 4878021 . PMID 23890009. doi:10.1016/j.chembiol.2013.05.010.
^ Sbrissa D, Naisan G, Ikonomov OC, Shisheva A. Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation. PLOS ONE. September 2018, 13 (9): e0204532. Bibcode:2018PLoSO..1304532S. PMC 6150535 . PMID 30240452. doi:10.1371/journal.pone.0204532 .
^ Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. March 2017, 129 (13): 1768–1778. PMC 5766845 . PMID 28104689. doi:10.1182/blood-2016-09-736892.
^ Nelson EA, Dyall J, Hoenen T, Barnes AB, Zhou H, Liang JY, et al. The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection. PLOS Neglected Tropical Diseases. April 2017, 11 (4): e0005540. PMC 5402990 . PMID 28403145. doi:10.1371/journal.pntd.0005540 .
^ Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, et al. Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. Journal of Virology. April 2019, 93 (8). PMC 6450122 . PMID 30700611. doi:10.1128/JVI.02185-18.
^ Ikonomov OC, Sbrissa D, Shisheva A. Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations. Toxicology and Applied Pharmacology. November 2019, 383: 114771. PMID 31628917. doi:10.1016/j.taap.2019.114771 .
^ Researchers use live virus to identify 30 existing drugs that could treat COVID-19 | SBP. www.sbpdiscovery.org. [2020-04-20].

[1] Billich A. Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency. IDrugs. January 2007, 10 (1): 53–9. PMID 17187316.

[2] Sands BE, Jacobson EW, Sylwestrowicz T, Younes Z, Dryden G, Fedorak R, Greenbloom S. Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease. Inflammatory Bowel Diseases. July 2010, 16 (7): 1209–18. PMID 19918967. S2CID 26012456. doi:10.1002/ibd.21159 .

[3] Krausz S, Boumans MJ, Gerlag DM, Lufkin J, van Kuijk AW, Bakker A, et al. Brief report: a phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis. Arthritis and Rheumatism. June 2012, 64 (6): 1750–5. PMID 22170479. doi:10.1002/art.34339.

[4] Shisheva A, Sbrissa D, Ikonomov O. Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells. Molecular and Cellular Biology. 1999, 19 (1): 623–634. PMC 83920 . PMID 9858586. doi:10.1128/mcb.19.1.623 .

[5] Cai X, Xu Y, Cheung AK, Tomlinson RC, Alcázar-Román A, Murphy L, et al. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chemistry & Biology. July 2013, 20 (7): 912–21. PMC 4878021 . PMID 23890009. doi:10.1016/j.chembiol.2013.05.010.

[6] Sbrissa D, Naisan G, Ikonomov OC, Shisheva A. Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation. PLOS ONE. September 2018, 13 (9): e0204532. Bibcode:2018PLoSO..1304532S. PMC 6150535 . PMID 30240452. doi:10.1371/journal.pone.0204532 .

[7] Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. March 2017, 129 (13): 1768–1778. PMC 5766845 . PMID 28104689. doi:10.1182/blood-2016-09-736892.

[8] Nelson EA, Dyall J, Hoenen T, Barnes AB, Zhou H, Liang JY, et al. The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection. PLOS Neglected Tropical Diseases. April 2017, 11 (4): e0005540. PMC 5402990 . PMID 28403145. doi:10.1371/journal.pntd.0005540 .

[9] Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, et al. Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. Journal of Virology. April 2019, 93 (8). PMC 6450122 . PMID 30700611. doi:10.1128/JVI.02185-18.

[10] Ikonomov OC, Sbrissa D, Shisheva A. Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations. Toxicology and Applied Pharmacology. November 2019, 383: 114771. PMID 31628917. doi:10.1016/j.taap.2019.114771 .

[11] Researchers use live virus to identify 30 existing drugs that could treat COVID-19 | SBP. www.sbpdiscovery.org. [2020-04-20].

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