"Saxagliptin (BMS-477118,Onglyza)" | 361442-04-8

• 物质功能分类: 原料药 - 循环系统用药 - 调节血脂药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: "Saxagliptin (BMS-477118,Onglyza)"
• 英文别名: (1R,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
• CAS: 361442-04-8
• 化学式: C₁₈H₂₅N₃O₂
• 分子量: 315.4
• InChiKey: QGJUIPDUBHWZPV-BBIKMUCQSA-N

物化性质

• 熔点：
  103 - 107°C
• 沸点：
  548.7±35.0 °C(Predicted)
• 密度：
  1.35
• 闪点：
  548.7℃
• 溶解度：
  可溶于DMSO（少量）、甲醇（少量）
• 蒸汽压力：
  4.19X10-11 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 1.11X10-18 atm-cu m/mol at 25 °C (est)
• 解离常数：
  pKa = 7.90 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  90.4
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

沙格列汀的代谢主要经由CYP3A4/5介导。在体外研究中，沙格列汀及其活性代谢物并未抑制CYP1A2、2A6、2B6、2C9、2C19、2D6、2E1或3A4，也未诱导CYP1A2、2B6、2C9或3A4。因此，沙格列汀预计不会改变通过这些酶代谢的同时给药的药物的代谢清除。沙格列汀是P-糖蛋白（P-gp）的底物，但不是P-gp的重要抑制剂或诱导剂。沙格列汀的主要代谢物也是一种DPP4抑制剂，其效力是沙格列汀的一半。

The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp. ... The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

萨格列汀是一种二肽基肽酶-4（DPP-4）抑制剂，用于治疗2型糖尿病。它已被指定为饮食和运动的辅助手段，以改善成年2型糖尿病患者的血糖控制。在多个临床环境中，萨格列汀治疗显著改善了与安慰剂相比的A1C水平。虽然有药物过量的报告，但大多数是意外的。大多数暴露于二肽类药物的成年和儿科/青少年患者在家中安全管理，在医疗机构评估时，不需要住院治疗。成人故意自伤的二肽类药物暴露在医疗机构管理，但在剂量高达成人治疗剂量的18倍时，很少导致住院或严重疾病。在健康受试者中，萨格列汀的剂量高达每天400毫克，持续2周，或是最推荐人类剂量的80倍（MRHD），没有剂量相关的临床不良反应，对校正QT间期（QTc）或心率没有临床意义的影响。动物研究：萨格列汀在食蟹猴四肢（尾巴、指端、阴囊和/或鼻子上的结痂和/或溃疡）产生了不良的皮肤变化。在剂量是MRHD的20倍时，皮肤病变是可逆的，但在某些情况下，在更高暴露时是不可逆的和坏死的。在发育研究中，引起母体毒性的更高剂量的萨格列汀也增加了胎儿吸收（大约是MRHD的2069倍和6138倍）。在约6138倍MRHD时，还观察到了对动情周期、生育力、排卵和着床的额外影响。萨格列汀在体外Ames细菌试验、体外原发性人淋巴细胞细胞遗传学试验、大鼠体内口服微核试验、大鼠体内口服DNA修复研究和大鼠外周血淋巴细胞体内/体外细胞遗传学研究中，无论是否经过代谢激活，都没有致突变或断裂作用。活性代谢物在体外Ames细菌试验中没有致突变作用。

IDENTIFICATION AND USE: Saxagliptin is a dipeptidyl peptidase-4(DPP-4) inihibitor used in the treatment of type-2 diabetes. It has been indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. HUMAN EXPOSURE AND TOXICITY: Treatment with saxagliptin provided significant improvements in A1C versus placebo. Cases of overdose have been reported but most were accidental. The majority of gliptin-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require hospitalization. Intentional self-harm-adult gliptin exposures were managed in a healthcare facility but rarely resulted in hospitalization or serious morbidity at doses up to 18 times the adult therapeutic dose. Saxagliptin in healthy subjects at doses up to 400 mg daily for 2 weeks, or 80 times the maximum recommended human dose (MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on corrected QT interval (QTc) or heart rate. ANIMAL STUDIES: Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible at doses 20 times the MRHD but in some cases were irreversible and necrotizing at higher exposures. In developmental studies, higher doses of saxagliptin that elicited maternal toxicity also increased fetal resorptions (approximately 2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility, ovulation, and implantation were observed at approximately 6138 times the MRHD. Saxagliptin was not mutagenic or clastogenic with or without metabolic activation in an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes. The active metabolite was not mutagenic in an in vitro Ames bacterial assay.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模临床试验中，使用沙格列汀治疗的血清酶升高率相似（

In large clinical trials, rates of serum enzyme elevations were similar with saxagliptin therapy (

来源:LiverTox

毒理性

• 相互作用

单次剂量联合使用沙格列汀（10毫克）和格列本脲（5毫克）分别增加了格列本脲和沙格列汀的峰血浆浓度16%和8%；格列本脲的AUC增加了6%，而沙格列汀的AUC减少了2%。制造商表示，由于沙格列汀和格列本脲联合使用时系统暴露的变化，不需要调整剂量。然而，在接受沙格列汀与磺酰脲类降糖药联合治疗的病人中，可能需要减少磺酰脲类的剂量，以降低低血糖的风险。

Concomitant administration of single doses of saxagliptin (10 mg) and glyburide (5 mg) increased peak plasma concentrations of glyburide and saxagliptin by 16 and 8%, respectively; the AUC of glyburide was increased by 6% and that of saxagliptin was decreased by 2%. The manufacturer states that no dosage adjustments are required because of changes in systemic exposures when saxagliptin and glyburide are given concomitantly. However, in patients receiving saxagliptin concomitantly with a sulfonylurea antidiabetic agent, a reduced dosage of the sulfonylurea may be required to reduce the risk of hypoglycemia.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

单次给予沙格列汀（100毫克）和盐酸二甲双胍（1克）联合给药时，沙格列汀的峰血浆浓度降低了21%，AUC降低了2%；二甲双胍的AUC和峰血浆浓度分别增加了20%和9%。

Concomitant administration of a single dose of saxagliptin (100 mg) and metformin hydrochloride (1 g) decreased the peak plasma concentration of saxagliptin by 21% and the AUC by 2%; metformin AUC and peak plasma concentration were increased by 20 and 9%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时给予沙格列汀（每日一次5毫克，共21天）和含有炔雌醇和诺孕酯的复方口服避孕药（炔雌醇35微克与诺孕酯0.25毫克固定组合，每日一次，共21天）并未显著改变炔雌醇或主要活性孕激素成分诺孕酯的稳态药代动力学。

Concurrent administration of saxagliptin (5 mg once daily for 21 days) and an estrogen-progestin combination contraceptive (ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.25 mg once daily for 21 days) did not appreciably alter the steady-state pharmacokinetics of ethinyl estradiol or the primary active progestin component, norelgestromin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

进行了一项单次给药、开放标签的研究，以评估在不同程度的慢性肾功能损害（每组 N=8）的患者中沙格列汀（10毫克剂量）的药代动力学，并将其与肾功能正常者进行比较。10毫克的剂量并不是一个批准的剂量。该研究包括了根据肌酐清除率分类为轻度（>50至=80 mL/min）、中度（30至=50 mL/min）和重度（<30 mL/min）的肾损害患者，以及需要血液透析的终末期肾病 患者。... 肾功能损害的程度并不影响沙格列汀或其活性代谢物的Cmax。在轻度肾功能损害的患者中，沙格列汀及其活性代谢物的AUC值分别比肾功能正常者高出20%和70%。由于这种程度的增加并不被认为是具有临床相关性的，因此不建议对轻度肾功能损害的患者调整剂量。在中度或重度肾功能损害的患者中，沙格列汀及其活性代谢物的AUC值分别比肾功能正常者高出高达2.1倍和4.5倍。为了达到与肾功能正常患者相似的沙格列汀及其活性代谢物的血浆暴露水平，建议中度、重度肾功能损害患者以及需要血液透析的终末期肾病患者每日一次服用2.5毫克的剂量。沙格列汀可通过血液透析去除。

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment (N=8 per group) compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (>50 to =80 mL/min), moderate (30 to =50 mL/min), and severe (<30 mL/min), as well as patients with end-stage renal disease on hemodialysis. ... The degree of renal impairment did not affect the Cmax of saxagliptin or its active metabolite. In subjects with mild renal impairment, the AUC values of saxagliptin and its active metabolite were 20% and 70% higher, respectively, than AUC values in subjects with normal renal function. Because increases of this magnitude are not considered to be clinically relevant, dosage adjustment in patients with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. To achieve plasma exposures of saxagliptin and its active metabolite similar to those in patients with normal renal function, the recommended dose is 2.5 mg once daily in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

沙格列汀通过肾脏和肝脏途径消除。在单次服用50毫克(14)-C-沙格列汀后，分别有24%、36%和75%的剂量以沙格列汀、其活性代谢物和总放射性物质的形式通过尿液排出。沙格列汀的平均肾清除率（约为230 mL/min）大于平均估计的肾小球滤过率（大约120 mL/min），这表明存在一些积极的肾脏排泄。总共有22%的给药放射性物质在粪便中回收，代表沙格列汀剂量中通过胆汁和/或胃肠系统中未吸收药物的部分。

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of (14)-C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (approximately 120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在禁食状态下口服给药后，沙格列汀被迅速吸收，沙格列汀及其主要代谢物的最大血浆浓度（Cmax）分别在大约2小时和4小时（Tmax）达到。沙格列汀及其主要代谢物的Cmax和AUC值随着沙格列汀剂量的增加而成比例增加，这种剂量比例性在400 mg剂量内观察到。在健康受试者中单次口服5 mg沙格列汀后，沙格列汀及其主要代谢物的平均血浆AUC值分别为78 ng*hr/mL和214 ng*hr/mL。相应的血浆Cmax值分别为24 ng/mL和47 ng/mL。沙格列汀Cmax和AUC的受试者内变异系数小于12%。

Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng*hr/mL and 214 ng*hr/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25,S26,S28,S36/37/39
• 危险类别码：
  R28,R38,R41,R48
• 海关编码：
  2933990090
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

沙格列汀简介

沙格列汀是一种用于治疗2型糖尿病的药物，通过餐后刺激胰腺产生更多胰岛素来发挥作用。由美国阿斯利康和百时美施贵宝公司联合研发成功，属于二肽基肽酶-4（DPP-4）抑制剂。2009年7月31日，该药物获美国FDA批准上市，用于成人2型糖尿病患者，同时配合饮食和运动使用。

沙格列汀最常见的副作用包括上呼吸道感染、尿路感染和头痛，其他副作用还包括过敏反应如皮疹和荨麻疹。

作用机制

沙格列汀通过阻断GLP-1的降解而发挥作用。GLP-1是一种肠内自然产生的激素，在摄入食物后促进胰岛素分泌，并加强周围组织对葡萄糖的利用度。单独使用或与二甲双胍、磺酰脲类和噻唑烷二酮类药物联合使用时，沙格列汀能改善血糖控制并降低低血糖的风险。

药理作用

沙格列汀是DPP-4竞争性抑制剂，可以减缓肠促胰岛激素的失活速度，增加其血液浓度。因此，在葡萄糖依赖的情况下减少2型糖尿病患者的空腹和餐后血糖水平。在进餐后，从小肠释放到血液中的肠促胰岛激素如胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素肽（GIP），促进胰腺β细胞以葡萄糖依赖的方式释放胰岛素，而DPP4则会使其失活。

适应症

沙格列汀可作为单药治疗或联合盐酸二甲双胍使用。在饮食和运动的基础上，它能够改善血糖控制：当单独使用二甲双胍无法达到理想效果时，可以与之联用以增强疗效。

合成方法

沙格列汀的合成首先由1-金刚烷甲酸合成前体物109，并由Boc-L焦谷氨酸乙酯合成前体113。随后使用这两种前体制备最终产物——沙格列汀。

图1展示了人工合成沙格列汀的化学反应路线图。

生物活性

Saxagliptin（Vadimezan, NSC 640488, ASA-404）是一种选择性、可逆的DPP4抑制剂，其IC50值为26 nM。体外研究显示，它对DPP4的抑制效力显著高于其他DPP4抑制剂vildagliptin或sitagliptin（Ki分别为13和18 nM），并且具有更高的特异性。

靶点

Target	Value
DPP-4	26 nM

体外研究

Saxagliptin对DPP4的抑制常数Ki为1.3 nM，比其他两个DPP4抑制剂vildagliptin或sitagliptin（分别为13和18 nM）有效约10倍。此外，与DPP8或DPP9酶相比，Saxagliptin对DPP4的选择性更高（分别是400-和75-倍）。其活性代谢物的效力仅为原药的一半。

体内研究

Saxagliptin减少了肠降血糖激素胰高血糖素样多肽-1的降解，并增强了其作用，与改善的β细胞功能及胰高血糖素分泌抑制相关。

反应信息

• 作为产物：
  描述：

  1-溴金刚烷 以95的产率得到"Saxagliptin (BMS-477118,Onglyza)"
  参考文献：
  名称：

  J. Med. Chem. 2005, 48, 5025-5037

  摘要：

  DOI：

文献信息

• [EN] PROCESS FOR PREPARING A DIPEPTIDYL PEPTIDASE IV INHIBITOR AND INTERMEDIATES EMPLOYED THEREIN<br/>[FR] PROCEDE DE PREPARATION D'UN INHIBITEUR DE LA DIPEPTIDYL PEPTIDASE IV ET PRODUITS INTERMEDIAIRES UTILISES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2005094323A2

  公开（公告）日：2005-10-13

  A process is provided for preparing a dipeptidyl peptidase IV inhibitor of the structure (10) wherein (3) is treated with TFAA in isopropyl acetate to protect the tertiary hydroxyl group as a trifluoroacetate group to form (4) (which is a novel intermediate) which is converted to acid chloride compound (5) (which is a novel compound) using Vilsmeier reagent or other chloro reagent and coupled with compound (6) in a heterogeneous mixture of ethyl acetate and aqueous bicarbonate to give compound (7).The N,O-bis(trifluoroacetyl) groups of compound (7) are deprotected to give free base compound (10).

  提供了一种制备二肽基肽酶IV抑制剂的方法，该抑制剂的结构为(10)，其中(3)在异丙酸酯中用三氟乙酸酐处理以保护三级羟基为三氟乙酸酯基形成(4)(这是一种新的中间体)，然后用威尔斯迈尔试剂或其他氯代试剂将其转化为酸氯化合物(5)(这是一种新的化合物)，并与化合物(6)在乙酸乙酯和碳酸氢钠的异相混合物中偶联，得到化合物(7)。化合物(7)的N,O-双(三氟乙酰)基团被去保护，得到自由碱基化合物(10)。
• Process for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein
  申请人：Sharma N. Padam

  公开号：US20050222242A1

  公开（公告）日：2005-10-06

  A process is provided for preparing a dipeptidyl peptidase IV inhibitor of the structure wherein is treated with TFAA in isopropyl acetate to protect the tertiary hydroxyl group as a trifluoroacetate group to form 4 (which is a novel intermediate) which is converted to acid chloride compound 5 (which is a novel compound) using Vilsmeier reagent or other chloro reagent and coupled with compound 6 in a heterogeneous mixture of ethyl acetate and aqueous bicarbonate to give compound 7 The N,O-bis(trifluoroacetyl) groups of compound 7 are deprotected to give free base compound 10.

  提供了一种制备二肽基肽酶IV抑制剂的方法，其中将结构式中的处理为三氟乙酸酯基以保护第三级羟基，形成4（这是一种新的中间体），然后使用Vilsmeier试剂或其他氯代试剂将其转化为酸氯化合物5（这是一种新的化合物），并与化合物6在乙酸乙酯和碳酸氢根的异相混合物中偶联，得到化合物7。化合物7的N，O-双（三氟乙酰基）基团被去保护，得到自由碱基化合物10。
• [EN] AMMONOLYSIS PROCESS FOR THE PREPARATION OF INTERMEDIATES FOR DPP IV INHIBITORS<br/>[FR] PROCEDE D'AMMONOLYSE DESTINE A LA PREPARATION D'INTERMEDIAIRES POUR DES INHIBITEURS IV DPP
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2006020664A2

  公开（公告）日：2006-02-23

  A process is provided for preparing the intermediate A in accordance with the following reaction sequence. The intermediate A is used in preparing DPP IV inhibitors which are useful in treating diabetes.

  提供了一种制备中间体A的方法，符合以下反应序列。中间体A用于制备DPP IV抑制剂，这些抑制剂对治疗糖尿病有用。
• [EN] PROCESS FOR PRODUCING A DIPEPTIDYL PEPTIDASE IV INHIBITOR<br/>[FR] PROCEDE DE PRODUCTION D'UN INHIBITEUR DE LA DIPEPTIDYL PEPTIDASE IV
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2005115982A1

  公开（公告）日：2005-12-08

  A process is provided for preparing the dipeptidyl peptidase of the structure (I) (also referred to as saxaglipitin) by direct dehydration, in one pot, of the amide II (II) by reacting amide II with phosphorus oxychloride in an organic solvent such as dichloromethane, quenching the reaction mixture with water to form the hydrochloric acid salt of I, and treating the hydrochloric acid salt with base to form the free base of I.

  提供了一种制备结构式(I)的二肽酶（也称为萨格列普汀）的方法，通过在有机溶剂如二氯甲烷中，将酰胺II（II）直接脱水反应制备。反应结束后，用水淬灭反应混合物以形成I的盐酸盐，并用碱处理盐酸盐以形成I的自由碱基。
• [EN] PROCESS FOR THE REDUCTIVE AMINATION OF a-KETO CARBOXYLIC ACIDS<br/>[FR] PROCÉDÉ D'AMINATION RÉDUCTRICE D'ACIDES ?-CÉTO-CARBOXYLIQUES
  申请人：SANDOZ AG

  公开号：WO2012028721A1

  公开（公告）日：2012-03-08

  The invention refers to a process for the reductive amination of α-keto carboxylic acids catalyzed by transition metal containing compounds.

  该发明涉及一种由含过渡金属化合物催化的α-酮羧酸还原胺化过程。