阿格列汀

阿格列汀
Alogliptin
系统（IUPAC）命名名称
	2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
临床数据
商品名	尼欣那（Nesina，ネシーナ）
妊娠分级	US: B (非人类研究中表明无风险) ; ;
给药途径	口服
合法状态
合法状态	处方药（℞-only）;
药代动力学数据
生物利用度	100%
蛋白结合度	20%
代谢	通过肝脏 (CYP2D6和CYP3A4）进行有限的代谢
生物半衰期	12–21小时
排泄	肾脏（主要）和粪便（少量）
识别信息
CAS注册号	850649-62-6
ATC代码	A10BH04
PubChem	CID 11450633
IUPHAR/BPS	6319
ChemSpider	9625485
UNII	JHC049LO86
KEGG	D06553
ChEBI	CHEBI:72323
ChEMBL	CHEMBL376359
其他名称	SYR-322
化学信息
化学式	C18H21N5O2
摩尔质量	339.39 g/mol
	SMILES N#Cc3ccccc3CN\1C(=O)N(C)C(=O)/C=C/1N2CCC[C@@H](N)C2; ;
	InChI InChI=1S/C18H21N5O2/c1-21-17(24)9-16(22-8-4-7-15(20)12-22)23(18(21)25)11-14-6-3-2-5-13(14)10-19/h2-3,5-6,9,15H,4,7-8,11-12,20H2,1H3/t15-/m1/s1 ; Key:ZSBOMTDTBDDKMP-OAHLLOKOSA-N ;

阿格列汀（英语：Alogliptin），商品名为尼欣那，是一种二肽基肽酶-4（DPP-4）抑制剂类口服抗糖尿病药^[1]，由日本武田药品研发于2005年。与其他治疗2型糖尿病的药物一样，阿格列汀不会增加心脏病与中风的风险。与其他列汀类药物相似，阿格列汀几乎不会导致体重增加，并且导致低血糖的风险相对较低，有着适度的降糖活性。阿格列汀和其他列汀类药物一样常与二甲双胍合用，用于无法单独用二甲双胍控制血糖的病人。^[2]

临床研究

阿格列汀是一种二肽基肽酶-4（DPP-4）抑制剂，可以减缓肠促胰岛素激素GLP-1（胰高血糖素样多肽-1）和GIP（葡萄糖依赖性促胰岛素多肽）的失活速度。当血糖浓度正常或升高时，GLP-1和GIP 可通过涉及环磷腺苷的细胞内信号途径增加胰腺β细胞合成并释放胰岛素。 ^[3]

已报告的不良反应

已报告的严重不良反应包括低血糖、急性胰腺炎、肝功能异常、黄疸、Stevens-Johnson综合征、多形性红斑、横纹肌溶解症、肠梗阻、间质性肺炎。^[4]。临床试验仅发现了较低几率会导致轻度的低血糖。^[5]^[6]^[7]。

阿格列汀不会导致体重、心血管疾病的风险和心脏病风险的增加。^[8]^[9]

销售许可情况

在III期临床试验取得了积极结果后，武田公司于2007年12月向FDA提交了新药申请。^[10]^[11]2008年11月，武田公司也在日本申请了审批，并且在2010年4月通过了审批。^[10]^[12]2012年，武田公司得到了FDA的负面回应，理由为需要更多的数据。阿格列汀最终于2013年通过了FDA的审批。

阿格列汀于2013年11月在中国上市，^[13]商品名为尼欣那（Nesina），是目前（2015年）国内最晚上市的列汀类药物。

代谢

阿格列汀不经过广泛代谢，给药剂量的60-71%以原型通过尿液排泄。

在口服给予[¹⁴C]阿格列汀后，检测到2种次要代谢产物，N-去甲基化代谢物M-I（<1%母体化合物）和N-乙酰化代谢产物M-II（<6%，母体化合物）。M-I为活性代谢产物，对DPP-4的抑制活性与母体化合物相似；M-II对DPP-4或其他DPP相关酶均不具有抑制活性。体外数据显示，CYP2D6和CYP3A4参与阿格列汀有限的代谢作用。

阿格列汀主要以(R)-异构体（>99%）形式存在，在体内少量转化为(S)-异构体或不发生转化。在25mg剂量水平，未检测到(S)-异构体。^[4]

引用

↑ Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassell, Daniel B.; Navre, Marc; Shi, Lihong; Skene, Robert J.; Asakawa, Tomoko; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney II, Stephen L. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem. 2007, 50 (10): 2297–2300. PMID 17441705. doi:10.1021/jm070104l.
↑ www.aace.com (PDF).
↑ News Releases | Takeda
↑ ^4.0 ^4.1 ネシーナ錠25mg／ネシーナ錠12.5mg／ネシーナ錠6.25mg 添付文书. 2014-10 [2015-03-26]. ^{[永久失效链接]}
↑ Seino, Yutaka; Fujita, Tetsuya; Hiroi, Shinzo; Hirayama, Masashi; Kaku, Kohei, Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study (abstract only), Current Medical Research and Opinion, 2011-09, 27 (9): 1781–1792 [2012-04-26], PMID 21806314, doi:10.1185/03007995.2011.599371
↑ Kutoh, Eiji; Ukai, Yasuhiro, Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial (abstract only), Endocrine, 20122012-01-17 [2012-04-26], PMID 22249941, doi:10.1007/s12020-012-9596-0
↑ Bosi, Emanuele; Ellis, G.C.; Wilson, C.A.; Fleck, P.R., Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study, Diabetes, Obesity and Metabolism, 2011-10, 13 (12): 1088–1096 (2011-10-27) [2012-04-26], doi:10.1111/j.1463-1326.2011.01463.x
↑ White WB, Cannon CP, Heller SR; et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 2013-10, 369 (14): 1327–35. PMID 23992602. doi:10.1056/NEJMoa1305889.
↑ White WB, Zannad F. Saxagliptin, alogliptin, and cardiovascular outcomes. N. Engl. J. Med. 2014-01, 370 (5): 484. PMID 24482824. doi:10.1056/NEJMc1313880.
↑ ^10.0 ^10.1 Grogan, Kevin, FDA wants yet more data on Takeda diabetes drug alogliptin, PharmaTimes (PharmaTimes), 2012-04-26, PharmaTimes online [2012-04-26]
↑ Takeda Submits New Drug Application for Alogliptin (SYR-322) in the U.S. (新闻稿). Takeda Pharmaceutical Company. 2008-01-04 [2008-01-09].
↑ GEN News Highlights: Takeda Pulls MAA for Type 2 Diabetes Therapy. Genetic Engineering & Biotechnology News. 2009-06-04.
↑ 新型Ⅱ型糖尿病治疗药物阿格列汀获准在中国上市.

[pmid17441705-1] Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassell, Daniel B.; Navre, Marc; Shi, Lihong; Skene, Robert J.; Asakawa, Tomoko; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney II, Stephen L. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem. 2007, 50 (10): 2297–2300. PMID 17441705. doi:10.1021/jm070104l.

[2] www.aace.com (PDF).

[3] News Releases | Takeda

[instruction-4] 4.0 ^4.1 ネシーナ錠25mg／ネシーナ錠12.5mg／ネシーナ錠6.25mg 添付文书. 2014-10 [2015-03-26]. ^{[永久失效链接]}

[seino2011-5] Seino, Yutaka; Fujita, Tetsuya; Hiroi, Shinzo; Hirayama, Masashi; Kaku, Kohei, Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study (abstract only), Current Medical Research and Opinion, 2011-09, 27 (9): 1781–1792 [2012-04-26], PMID 21806314, doi:10.1185/03007995.2011.599371

[kutoh2012-6] Kutoh, Eiji; Ukai, Yasuhiro, Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial (abstract only), Endocrine, 20122012-01-17 [2012-04-26], PMID 22249941, doi:10.1007/s12020-012-9596-0

[bosi2011-7] Bosi, Emanuele; Ellis, G.C.; Wilson, C.A.; Fleck, P.R., Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study, Diabetes, Obesity and Metabolism, 2011-10, 13 (12): 1088–1096 (2011-10-27) [2012-04-26], doi:10.1111/j.1463-1326.2011.01463.x

[8] White WB, Cannon CP, Heller SR; et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 2013-10, 369 (14): 1327–35. PMID 23992602. doi:10.1056/NEJMoa1305889.

[9] White WB, Zannad F. Saxagliptin, alogliptin, and cardiovascular outcomes. N. Engl. J. Med. 2014-01, 370 (5): 484. PMID 24482824. doi:10.1056/NEJMc1313880.

[grogan2012-10] 10.0 ^10.1 Grogan, Kevin, FDA wants yet more data on Takeda diabetes drug alogliptin, PharmaTimes (PharmaTimes), 2012-04-26, PharmaTimes online [2012-04-26]

[takedapr28864-11] Takeda Submits New Drug Application for Alogliptin (SYR-322) in the U.S. (新闻稿). Takeda Pharmaceutical Company. 2008-01-04 [2008-01-09].

[geneng2009-12] GEN News Highlights: Takeda Pulls MAA for Type 2 Diabetes Therapy. Genetic Engineering & Biotechnology News. 2009-06-04.

[13] 新型Ⅱ型糖尿病治疗药物阿格列汀获准在中国上市.

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