saxagliptin

• 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
• 英文别名: (1S,3S,5S)-2-[(2S)-2-amino-2-[(5R,7R)-3-hydroxy-1-adamantyl]acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
• 化学式: C₁₈H₂₅N₃O₂
• 分子量: 315.415
• InChiKey: QGJUIPDUBHWZPV-HXDJVDLCSA-N

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的显著抑制剂或诱导剂。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。故意自伤的成年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病态。在健康受试者中，每日剂量高达400毫克，持续2周，或高达推荐人类最大剂量（MRHD）的80倍，萨格列汀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（尾部、指端、阴囊和/或鼻子的结痂和/或溃疡）产生不良反应。在剂量为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，更高剂量的萨格列汀诱发了母体毒性，也增加了胎儿吸收率（大约是MRHD的2069倍和6138倍）。在大约6138倍MRHD时，还观察到了对发情周期、生育力、排卵和着床的额外影响。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，萨格列汀在有或没有代谢激活的情况下均不具有致突变性或断裂性。活性代谢物在体外Ames细菌试验中不具有致突变性。

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）的联合给药，使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形式在尿液中排出。沙格列汀的平均肾清除率（约230毫升/分钟）大于平均估计的肾小球滤过率（大约120毫升/分钟），这表明存在一些积极的肾脏排泄。总共有22%的给药放射性在粪便中回收，代表沙格列汀剂量中通过胆汁和/或未吸收的药物从胃肠道排出的部分。

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)

反应信息

• 作为产物：
  描述：

  tert-butyl N-[(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl]-1-[(5R,7R)-3-hydroxy-1-adamantyl]-2-oxoethyl]carbamate 在 盐酸 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 水 、 乙酸乙酯 、 异丙醇 为溶剂， 反应 5.5h， 生成 saxagliptin
  参考文献：
  名称：

  一种氨基保护的3-羟基金刚烷甘氨酸苯并噻 唑-2-硫醇活性酯、其制备方法及应用

  摘要：

  本发明涉及一种氨基保护的3‑羟基金刚烷甘氨酸苯并噻唑‑2‑硫醇活性酯、其制备方法及应用，该硫醇活性酯通过氨基保护的3‑羟基金刚烷甘氨酸与二硫化二苯并噻唑反应得到，本发明同时提供了该化合物在制备沙格列汀中间体和制备沙格列汀中的应用。本发明提供了一种全新的化学结构，其制备方法简单，成本低，用于沙格列汀的制备能够有效简化制备工艺，反应温和，具有广阔的推广前景。

  公开号：

  CN106349185B

文献信息

• 一种氨基保护的3-羟基金刚烷甘氨酸苯并噻 唑-2-硫醇活性酯、其制备方法及应用
  申请人：河北科技大学

  公开号：CN106349185B

  公开（公告）日：2018-07-06

  本发明涉及一种氨基保护的3‑羟基金刚烷甘氨酸苯并噻唑‑2‑硫醇活性酯、其制备方法及应用，该硫醇活性酯通过氨基保护的3‑羟基金刚烷甘氨酸与二硫化二苯并噻唑反应得到，本发明同时提供了该化合物在制备沙格列汀中间体和制备沙格列汀中的应用。本发明提供了一种全新的化学结构，其制备方法简单，成本低，用于沙格列汀的制备能够有效简化制备工艺，反应温和，具有广阔的推广前景。