Hgegtftsdlskqmeeeavrlfiewlknggpssgsppps-NH2

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: Hgegtftsdlskqmeeeavrlfiewlknggpssgsppps-NH2
• 英文别名: (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]acetyl]amino]-5-oxopentanoic acid
• 化学式: C₁₈₄H₂₈₂N₅₀O₆₀S
• 分子量: 4187.0
• InChiKey: HTQBXNHDCUEHJF-XWLPCZSASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -21.3
• 重原子数：
  295
• 可旋转键数：
  134
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  1780
• 氢给体数：
  57
• 氢受体数：
  66

ADMET

毒理性

• 肝毒性

利拉鲁肽引起的肝脏损伤必须很罕见，如果真的发生的话。在大型临床试验中，利拉鲁肽治疗引起的血清酶升高并不比安慰剂或比较剂更常见，而且没有报告出现临床明显的肝脏损伤。自从获得许可以来，没有发表过由于利拉鲁肽导致的肝毒性的病例报告，产品标签上也没有列出肝脏损伤作为不良事件。利拉鲁肽与罕见的急性胰腺炎病例有关联，但即使这种并发症通常也不伴有血清胆红素和转氨酶水平的升高。

Liver injury due to exenatide must be rare, if it occurs at all. In large clinical trials, serum enzyme elevations were no more common with exenatide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there have been no published case reports of hepatotoxicity due to exenatide and the product label does not list liver injury as an adverse event. Exenatide has been linked to rare instances of acute pancreatitis, but even this complication is usually not associated with elevations in serum bilirubin and aminotransferase levels.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：艾塞那肽

Compound:exenatide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

在单次给药Bydureon后，艾塞那肽从微球中大约在10周内释放。首先是一段表面结合的艾塞那肽释放期，随后是微球中艾塞那肽的逐渐释放，这导致在血浆中大约在第2周和第6至7周分别出现两个艾塞那肽的峰值，这代表了微球的水化和侵蚀。在开始每周一次（每周）给药2 mg Bydureon后，观察到血浆中艾塞那肽浓度在6到7周内逐渐增加。在6到7周后，平均艾塞那肽浓度在大约300 pg/mL左右，在每周一次（每周）给药间隔内维持，表明已达到稳态。

Following a single dose of Bydureon, exenatide is released from the microspheres over approximately 10 weeks. There is an initial period of release of surface-bound exenatide followed by a gradual release of exenatide from the microspheres, which results in two subsequent peaks of exenatide in plasma at around week 2 and week 6 to 7, respectively, representing the hydration and erosion of the microspheres. Following initiation of once every 7 days (weekly) administration of 2 mg Bydureon, gradual increase in the plasma exenatide concentration is observed over 6 to 7 weeks. After 6 to 7 weeks, mean exenatide concentrations of approximately 300 pg/mL were maintained over once every 7 days (weekly) dosing intervals indicating that steady state was achieved.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

非临床研究表明，艾塞那肽主要通过肾小球滤过随后发生蛋白水解降解而被消除。艾塞那肽在人中的平均表观清除率为9.1升/小时，平均终末半衰期为2.4小时。艾塞那肽的这些药代动力学特征与剂量无关。在大多数个体中，艾塞那肽浓度在给药后大约10小时内可被测量到。

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hr and the mean terminal half-life is 2.4 hr. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hr post-dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

皮下注射单剂量的百泌达后，艾塞那肽的平均表观分布体积为28.3升。

The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在2型糖尿病患者中，接受艾塞那肽的皮下注射后，艾塞那肽达到中位血浆峰浓度的时间为2.1小时。注射10微克Byetta剂量的艾塞那肽后，平均峰浓度（Cmax）为211皮克/毫升，总体平均药时曲线下面积（AUC0-inf）为1036皮克·小时/毫升。在5微克到10微克的疗法剂量范围内，艾塞那肽的暴露量（AUC）与剂量成正比增加。在同一剂量范围内，Cmax值的增加幅度小于剂量增加的比例。在腹部、大腿或上臂进行Byetta的皮下注射可以相似地达到药物暴露。

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hr. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg hr/mL following SC administration of a 10 ug dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 ug to 10 ug. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or upper arm.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO
  申请人：Jones Robert M.

  公开号：US20130023494A1

  公开（公告）日：2013-01-24

  The present invention relates to compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single agent or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an SGLT2 inhibitor, or an alpha-glucosidase inhibitor, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing a blood incretin level; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及式(Ia)化合物及其药学上可接受的盐、溶剂和水合物，可作为单一药剂或与一种或多种其他药物剂合用，例如DPP-IV抑制剂、双胍类药物、SGLT2抑制剂或α-葡萄糖苷酶抑制剂，用于治疗选择自：GPR119受体相关疾病；通过增加血液肠促素水平改善的状况；代谢相关疾病；2型糖尿病；肥胖症；以及相关并发症的障碍。
• Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
  申请人：Jones Robert M.

  公开号：US20140038889A1

  公开（公告）日：2014-02-06

  The present invention relates to the GPR119 agonist, 1-methylcyclopropyl 4-(5-fluoro-6-(2-methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidin-4-yloxy)piperidine-1-carboxylate (Compound 1): and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing the secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及GPR119激动剂，1-甲基环丙基4-(5-氟-6-(2-甲基-6-(甲基磺酰基)吡啶-3-氧基)嘧啶-4-氧基)哌啶-1-羧酸甲酯（化合物1）及其药学上可接受的盐、溶剂合物和水合物，它们可作为单一药物或与一个或多个其他药物联合使用，例如DPP-IV抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、噻唑烷二酮或抗糖尿病肽类似物，用于治疗例如GPR119受体相关疾病；通过增加肠促素分泌改善的病症；通过增加血液肠促素水平改善的病症；低骨密度症状；神经系统疾病；代谢相关疾病；2型糖尿病；肥胖症及相关并发症。
• Modulators of the GPR119 receptor and the treatment of disorders related thereto
  申请人：Jones Robert M.

  公开号：US10894787B2

  公开（公告）日：2021-01-19

  The present invention relates to the GPR119 receptor agonists: 3-fluoro-4-(5-fluoro-6-(4-3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-imethylbenzamide; 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide; and 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single pharmaceutical agent or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPRI19-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及 GPR119 受体激动剂：3-氟-4-(5-氟-6-(4-3-(2-氟丙烷-2-基)-1,2,4-恶二唑-5-基)哌啶-1-基)嘧啶-4-基氨基)-N,N-亚甲基苯甲酰胺；3-氟-4-(5-氟-6-(4-(3-(2-氟丙烷-2-基)-1,2,4-恶二唑-5-基)哌啶-1-基)嘧啶-4-基氨基)-N-甲基苯甲酰胺；和 3-氟-4-(5-氟-6-(4-(3-(2-氟丙烷-2-基)-1,2,4-恶二唑-5-基)哌啶-1-基)嘧啶-4-基氨基)苯甲酰胺，及其药学上可接受的盐、溶液剂和水合物，可作为单一药剂或与一种或多种其他药剂联合使用、例如，DPP-IV 抑制剂、双胍类、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺酰脲类、SGLT2 抑制剂、梅格利肽、噻唑烷二酮或抗糖尿病肽类似物，用于治疗例如选自以下药物的疾病：GPRI19受体相关疾病；通过增加增量素分泌而改善的疾病；通过增加血液中增量素水平而改善的疾病；以低骨量为特征的疾病；神经系统疾病；代谢相关疾病；2型糖尿病；肥胖症；以及与之相关的并发症。