Semaksanib
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| Rumus | C15H14N2O |
| Massa molar | 238,29 g·mol−1 |
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Semaksanib (INN,[1] dengan nama kode pengembangan SU5416) adalah obat penghambat tirosin kinase yang dirancang oleh SUGEN sebagai terapi kanker.
Penelitian
Pada bulan Februari 2002, Pharmacia yang saat itu merupakan induk dari Sugen, mengakhiri uji klinis fase III semaksanib secara prematur dalam pengobatan kanker usus besar lanjut karena hasil yang mengecewakan.[2] Penelitian lain, pada fase yang lebih awal, telah dilakukan sejak saat itu.[3][4] Namun, karena prospek penghambat tirosin kinase generasi berikutnya dan ketidakefektifan semaksanib dalam uji klinis, pengembangan obat lebih lanjut telah dihentikan.[5] Senyawa terkaitny yakni SU11248 (sunitinib) dikembangkan lebih lanjut oleh Sugen dan kemudian oleh Pfizer, dan menerima persetujuan FDA untuk pengobatan karsinoma ginjal pada bulan Januari 2006.[6]
Ketika dikombinasikan dengan paparan kronis terhadap hipoksia, SU5416 menginduksi hipertensi paru yang parah pada tikus dan mencit. Properti ini telah dimanfaatkan untuk mengembangkan serangkaian model hewan pengerat hipertensi arteri paru yang berguna, meskipun kontroversial, yang pertama dan paling baik dikarakterisasi adalah model mencit Sugen/Hypoxia (SuHx).[7][8]
Sintesis
Reaksi Vilsmeier–Haack pada 2,4-dimetilpirol (1) menghasilkan aldehida (2). Kondensasi Knoevenagel dari zat antara ini dengan oksindola (3) dengan adanya basa menghasilkan semaksanib.[9][10][11]
Referensi
- ^ World Health Organization (2001). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85". WHO Drug Information. 15 (2). "Full text" (PDF). Diarsipkan dari asli (PDF) tanggal 2007-03-16. (244 KiB)
- ^ "Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials" (Press release). February 8, 2002. Diakses tanggal 2007-03-20.
- ^ O'Donnell A, Padhani A, Hayes C, Kakkar AJ, Leach M, Trigo JM, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I (October 2005). "A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points". British Journal of Cancer. 93 (8): 876–83. doi:10.1038/sj.bjc.6602797. PMC 2361651. PMID 16222321.
- ^ Lockhart AC, Cropp GF, Berlin JD, Donnelly E, Schumaker RD, Schaaf LJ, Hande KR, Fleischer AC, Hannah AL, Rothenberg ML (April 2006). "Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer". American Journal of Clinical Oncology. 29 (2): 109–15. doi:10.1097/01.coc.0000199882.53545.ac. PMID 16601426. S2CID 26566099.
- ^ Hoff PM, Wolff RA, Bogaard K, Waldrum S, Abbruzzese JL (February 2006). "A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma". Japanese Journal of Clinical Oncology. 36 (2): 100–3. doi:10.1093/jjco/hyi229. PMID 16449240.
- ^ "FDA approves new treatment for gastrointestinal and kidney cancer". U.S. Food and Drug Administration (FDA). 2006. Diarsipkan dari asli tanggal 3 February 2006.
- ^ Vitali SH, Hansmann G, Rose C, Fernandez-Gonzalez A, Scheid A, Mitsialis SA, Kourembanas S (December 2014). "The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up". Pulm Circ. 4 (4): 619–29. doi:10.1086/678508. PMC 4278622. PMID 25610598.
- ^ Voelkel NF, Bogaard HJ (2021). "Sugen, hypoxia and the lung circulation". Pulm Circ. 11 (4) 20458940211051188. doi:10.1177/20458940211051188. PMC 8493318. PMID 34631012.
- ^ Sun L, Tran N, Tang F, App H, Hirth P, McMahon G, Tang C (July 1998). "Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases". Journal of Medicinal Chemistry. 41 (14): 2588–2603. doi:10.1021/jm980123i. PMID 9651163.
- ^ Lubkoll J, Millemaggi A, Perry A, Taylor RJ (2010). "Tandem Horner–Wadsworth–Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756". Tetrahedron. 66 (33): 6606–6612. doi:10.1016/j.tet.2010.03.018.
- ^ Blanche EA, Maskell L, Colucci MA, Whatmore JL, Moody CJ (2009). "Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles". Tetrahedron. 65 (25): 4894–4903. doi:10.1016/j.tet.2009.04.014.
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