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;
识别信息
	IUPAC命名法 N-[(E)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine; ;
CAS号	541550-19-0
PubChem CID	10173277;
DrugBank	05611;
ChemSpider	8348782;
UNII	GFW2K84S4L;
ECHA InfoCard	100.237.985
化学信息
化学式	C23H26N6O2
摩尔质量	418.50 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	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；开发代号：STA-5326），或译阿匹莫德，是一种最初被确定为可以抑制白细胞介素 IL-12和IL-23产生的药物，并被开发用于口服治疗克罗恩病和类风湿性关节炎等自身免疫性疾病，^[1]但是临床试验结果令人失望，而且这些药物的开发申请也暂停了。^[2]^[3]

随后，人们发现阿吡莫德还有另一种作用方式，即作为脂质激酶PIKfyve（英语：PIKFYVE）的抑制剂。^[4]^[5]PIKfyve产生两种脂质，即PtdIns5P和PtdIns(3,5)P2。在体外测定中，它们的合成可被阿吡莫德（ID50 = 0.4 nM）有效地抑制。在人胚胎肾细胞中施用阿匹莫德（100 nM；60分钟）可显着降低PtdIns5P和PtdIns(3,5)P2的水平。^[6]

最近，阿吡莫德已被提议用作潜在的抗病毒和抗癌药物，可用于治疗非霍奇金淋巴瘤以及埃博拉病毒病、拉沙热和COVID-19等病毒性疾病。^[7]^[8]^[9]^[10]^[11]

参考资料[编辑]

^ 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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