阿莫雷生

**阿莫雷生**
臨床資料
其他名稱	ACT-078573
給藥途徑	口服
藥物類別（英語：Drug class）	食慾素拮抗劑（英語：Orexin antagonist）
ATC碼	未分配;
藥物動力學數據
藥物代謝	肝
生物半衰期	13–19小時
識別資訊
	IUPAC命名法 (2R)-2-[(1S)- 6,7-Dimethoxy-12-[4-(trifluoromethyl)phenyl]ethyl3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylacetamide; ;
CAS號	871224-64-5（; 913358-93-7 (HCl)）
PubChem CID	23727689;
IUPHAR/BPS	2886;
ChemSpider	21377865 ;
UNII	9KCW39P2EI;
KEGG	D09964 ;
ChEMBL	ChEMBL455136 ;
CompTox Dashboard（英語：CompTox Chemicals Dashboard） (EPA)	DTXSID801007352 ;
化學資訊
化學式	C29H31F3N2O3
摩爾質量	512.57 g·mol−1
3D模型（JSmol（英語：JSmol））	交互式圖像;
	SMILES CNC(=O)[C@@H](C1=CC=CC=C1)N2CCC3=CC(=C(C=C3[C@@H]2CCC4=CC=C(C=C4)C(F)(F)F)OC)OC;
	InChI InChI=1S/C29H31F3N2O3/c1-33-28(35)27(20-7-5-4-6-8-20)34-16-15-21-17-25(36-2)26(37-3)18-23(21)24(34)14-11-19-9-12-22(13-10-19)29(30,31)32/h4-10,12-13,17-18,24,27H,11,14-16H2,1-3H3,(H,33,35)/t24-,27+/m0/s1 ; Key:DKMACHNQISHMDN-RPLLCQBOSA-N ;

阿莫雷生（英語：Almorexant；開發代號：ACT-078573），或譯阿莫倫特，是一種食慾素拮抗劑（英語：Orexin antagonist），可作為食慾素受體（英語：Orexin receptor）（OX₁（英語：Hypocretin (orexin) receptor 1）和OX₂（英語：Hypocretin (orexin) receptor 2））的競爭性拮抗劑。該藥物由製藥公司Actelion（英語：Actelion）和葛蘭素史克開發，用於治療失眠。^[3]由於在試驗中觀察到肝酶短暫升高後對阿莫雷生的肝臟安全性存在擔憂，該藥物的開發於2011年1月被中止。^[4]^[5]

藥理學[編輯]

藥效學[編輯]

阿莫雷生是一種競爭性雙重OX₁（英語：Hypocretin (orexin) receptor 1）和OX₂（英語：Hypocretin (orexin) receptor 2）受體拮抗劑，它可選擇性抑制OX₁和OX₂受體激活所產生的功能性後果，例如細胞內Ca²⁺動員。它與食慾素受體的解離速度非常緩慢，這可能會延長其作用持續時間。^[6]

歷史[編輯]

阿莫雷生最初由Actelion開發，從2007年開始被報道為一種潛在的重磅藥物，因為其新穎的作用機制（食慾素受體拮抗作用）被認為能產生比傳統的苯二氮䓬類藥物和Z類藥物（英語：Nonbenzodiazepine）更好的睡眠質量和更少的副作用。這些傳統藥物主導了數十億美元的失眠藥物市場。^[7]

2008年，葛蘭素史克以1.47億美元的首期付款從Actelion手中購買了阿莫雷生的開發和營銷權。^[8]如果該藥物成功完成臨床開發並獲得美國食品藥品監督管理局批准，這筆交易的價值估計為32億美元。^[9]葛蘭素史克和Actelion繼續共同開發該藥物，並於2009年11月完成了III期臨床試驗。^[10]

然而在2011年1月，Actelion和葛蘭素史克宣佈，由於阿莫雷生的副作用，他們將放棄對其的開發。^[4]^[11]

2014年，Actelion的研究人員發表的研究表明，阿莫雷生具有輕微的濫用潛力，但濫用潛力明顯低於唑吡坦。^[12]

參考資料[編輯]

^ Andrews SP, Aves SJ, Christopher JA, Nonoo R. Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities. Current Topics in Medicinal Chemistry. 2016, 16 (29): 3438–3469. PMID 26416477. doi:10.2174/1568026616666150929111607.
^ Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, Dingemanse J. Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clinical Pharmacology and Therapeutics. May 2010, 87 (5): 593–600. PMID 20376002. S2CID 37675356. doi:10.1038/clpt.2010.19.
^ Neubauer DN. Almorexant, a dual orexin receptor antagonist for the treatment of insomnia. Current Opinion in Investigational Drugs. January 2010, 11 (1): 101–110. PMID 20047164.
^ ^4.0 ^4.1 GSK and Actelion discontinue clinical development of almorexant. GSK press release. 28 January 2011. （原始內容存檔於2011-07-04）.
^ Hoch M, van Gorsel H, van Gerven J, Dingemanse J. Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant. Journal of Clinical Pharmacology. September 2014, 54 (9): 979–986. PMID 24691844. S2CID 40714628. doi:10.1002/jcph.297.
^ Jacobson LH, Hoyer D, de Lecea L. Hypocretins (orexins): The ultimate translational neuropeptides. Journal of Internal Medicine. May 2022, 291 (5): 533–556. PMID 35043499. S2CID 248119793. doi:10.1111/joim.13406.
^ Sleeping Beautifully. CBS Business Network. 24 September 2007.
^ Actelion Sells Glaxo Almorexant Sleep Medicine Rights. Bloomberg. 14 July 2008 [2024-02-29]. （原始內容存檔於2012-11-05）.
^ Actelion's top dollar deal leaves doubts, and little on the horizon. EP Vantage. 14 July 2008.
^ Clinical trial number NCT00608985 for "Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1)" at ClinicalTrials.gov
^ Actelion and GSK Discontinue Clinical Development of Almorexant. Actelion press release. 28 January 2011. （原始內容存檔於2011-03-03）.
^ Cruz, Hans G.; Hoever, Petra; Chakraborty, Bijan; Schoedel, Kerri; Sellers, Edward M.; Dingemanse, Jasper. Assessment of the Abuse Liability of a Dual Orexin Receptor Antagonist: A Crossover Study of Almorexant and Zolpidem in Recreational Drug Users. CNS Drugs. April 2014, 28 (4): 361–372. doi:10.1007/s40263-014-0150-x.

外部連結[編輯]

Actelion's official website

[pmid26416477-1] Andrews SP, Aves SJ, Christopher JA, Nonoo R. Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities. Current Topics in Medicinal Chemistry. 2016, 16 (29): 3438–3469. PMID 26416477. doi:10.2174/1568026616666150929111607.

[pmid20376002-2] Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, Dingemanse J. Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clinical Pharmacology and Therapeutics. May 2010, 87 (5): 593–600. PMID 20376002. S2CID 37675356. doi:10.1038/clpt.2010.19.

[pmid20047164-4] Neubauer DN. Almorexant, a dual orexin receptor antagonist for the treatment of insomnia. Current Opinion in Investigational Drugs. January 2010, 11 (1): 101–110. PMID 20047164.

[GSK-PR_2011-01-5] 4.0 ^4.1 GSK and Actelion discontinue clinical development of almorexant. GSK press release. 28 January 2011. （原始內容存檔於2011-07-04）.

[6] Hoch M, van Gorsel H, van Gerven J, Dingemanse J. Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant. Journal of Clinical Pharmacology. September 2014, 54 (9): 979–986. PMID 24691844. S2CID 40714628. doi:10.1002/jcph.297.

[pmid35043499-7] Jacobson LH, Hoyer D, de Lecea L. Hypocretins (orexins): The ultimate translational neuropeptides. Journal of Internal Medicine. May 2022, 291 (5): 533–556. PMID 35043499. S2CID 248119793. doi:10.1111/joim.13406.

[8] Sleeping Beautifully. CBS Business Network. 24 September 2007.

[9] Actelion Sells Glaxo Almorexant Sleep Medicine Rights. Bloomberg. 14 July 2008 [2024-02-29]. （原始內容存檔於2012-11-05）.

[10] Actelion's top dollar deal leaves doubts, and little on the horizon. EP Vantage. 14 July 2008.

[11] Clinical trial number NCT00608985 for "Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1)" at ClinicalTrials.gov

[12] Actelion and GSK Discontinue Clinical Development of Almorexant. Actelion press release. 28 January 2011. （原始內容存檔於2011-03-03）.

[13] Cruz, Hans G.; Hoever, Petra; Chakraborty, Bijan; Schoedel, Kerri; Sellers, Edward M.; Dingemanse, Jasper. Assessment of the Abuse Liability of a Dual Orexin Receptor Antagonist: A Crossover Study of Almorexant and Zolpidem in Recreational Drug Users. CNS Drugs. April 2014, 28 (4): 361–372. doi:10.1007/s40263-014-0150-x.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]