nateglinide | 105746-37-0

• 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: nateglinide
• 英文别名: N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine；(2R)-3-phenyl-2-[(4-propan-2-ylcyclohexanecarbonyl)amino]propanoic acid
• CAS: 105746-37-0
• 化学式: C₁₉H₂₇NO₃
• 分子量: 317.428
• InChiKey: OELFLUMRDSZNSF-OFLPRAFFSA-N

物化性质

• 熔点：
  230-232 °C
• 沸点：
  527.6±39.0 °C(Predicted)
• 密度：
  1.104±0.06 g/cm3(Predicted)
• 溶解度：
  Practically insoluble
• 碰撞截面：
  178.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

肝脏，通过细胞色素P450同工酶CYP2C9（70%）和CYP3A4（30%）。代谢通过羟基化随后进行葡萄糖醛酸化。主要代谢物与那格列奈相比抗糖尿病活性较低，但异戊烯次要代谢物的抗糖尿病活性与那格列奈相当。

Hepatic, via cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). Metabolism is via hydroxylation followed by glucuronidation. The major metabolites have less antidiabetic activity than nateglinide, but the isoprene minor metabolite has antidiabetic activity comparable to that of nateglinide.

来源:DrugBank

代谢

那格列奈已知的人类代谢物包括(2S,3S,4S,5R)-3,4,5-三羟基-6-[(2R)-3-苯基-2-[(4-丙烷-2-基环己烷甲酰基)氨基]丙酰氧基]氧杂环己烷-2-羧酸。

Nateglinide has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[(2R)-3-phenyl-2-[(4-propan-2-ylcyclohexanecarbonyl)amino]propanoyl]oxyoxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

在几项大型临床试验中，与安慰剂相比，使用那格列奈导致血清转氨酶升高的情况并不常见。发生的酶水平升高是无症状的，并且在停止治疗后迅速恢复。自从那格列奈获得批准并广泛使用以来，FDA和药品赞助商收到了关于临床明显的肝损伤归因于那格列奈的报告。然而，这些案例都没有被发表，损伤的临床特征、发病时间、病程和结果也尚未描述。与那格列奈相似的药物米格列奈的类似物瑞格列奈在罕见病例中被怀疑与胆汁淤积性或混合性肝炎有关，但那格列奈是否会导致类似的肝损伤尚不清楚。因此，那格列奈很可能是导致临床明显肝病非常罕见的原因。

In several large clinical trials, serum aminotransferase elevations were no more common with nateglinide than with placebo. The enzyme elevations that occurred were asymptomatic and resolved rapidly with stopping therapy. Since its approval and with wide scale use, the FDA and the sponsor have received reports of clinically apparent liver injury attributed to nateglinide. However, none of these cases has been published and the clinical features, time to onset, course and outcome of the injury have not been described. The metiglinide analogue repaglinide has been impicated in rare cases of cholestatic or mixed hepatitis, but whether nateglinide liver injury is similar is not known. Thus, nateglinide is likely to be a very rare cause of clinically apparent liver disease.

来源:LiverTox

毒理性

• 药物性肝损伤

那格列奈

Compound:nateglinide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

在饭前口服给药后迅速吸收，绝对生物利用度估计大约为73%。口服给药后，血浆峰浓度通常在1小时内出现。作用开始时间小于20分钟，作用持续时间大约为4小时。

Rapidly absorbed following oral administration prior to a meal, absolute bioavailability is estimated to be approximately 73%. Peak plasma concentrations generally occur within 1 hour of oral administration. Onset of action is <20 minutes and the duration of action is approximately 4 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

尿液（83%）和粪便（10%）

Urine (83%) and feces (10%)

来源:DrugBank

吸收、分配和排泄

• 分布容积

10升在健康受试者中

10 liters in healthy subjects

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  nateglinide 以52%的产率得到
  参考文献：
  名称：

  SHINKAI, HISASHI;NISHIKAWA, MASAHIKO;SATO, YUSUKE;TOI, KOJI;KUMASHIRO, IZ+, J. MED. CHEM., 32,(1989) N, C. 1436-1441

  摘要：

  DOI：
• 作为产物：
  描述：

  D-苯丙氨酸 生成 nateglinide
  参考文献：
  名称：

  TOESIMA, SIGEHRU;SEHDO, TOSIKO;NIIMI, XISASI;TOI, KODZI;KUMASIRO, IDZUMI

  摘要：

  DOI：

文献信息

• Aromatic amine derivative and use thereof
  申请人：Taniguchi Takahiko

  公开号：US20090325956A1

  公开（公告）日：2009-12-31

  The present invention provides a novel SCD inhibitor. An SCD inhibitor containing a compound represented by the formula [I] wherein ring A is an optionally substituted aromatic ring, ring B is an optionally substituted ring, ring C is an optionally substituted aromatic ring, R is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and X is a spacer having 1 to 5 atoms in the main chain, or a salt thereof, or a prodrug thereof.

  本发明提供了一种新型SCD抑制剂。一种包含由下式[I]表示的化合物的SCD抑制剂 其中环A是可选择取代的芳香环，环B是可选择取代的环，环C是可选择取代的芳香环，R是氢原子，可选择取代的碳氢基团或可选择取代的杂环基团，X是具有主链中1到5个原子的间隔物，或其盐，或其前药。
• Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
  申请人：Akerman Michelle

  公开号：US20060004012A1

  公开（公告）日：2006-01-05

  The present invention provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula Q-L 1 -P-L 2 -M-X-L 3 -A wherein the definitions of the variables Q, L 1 , P, L 2 , M, X, L 3 and A are provided herein. The present invention also provides compositions and methods for use of the compounds, for instance, for treatment of type II diabetes.

  本发明提供了一种有用的化合物，例如，用于调节受试者体内胰岛素水平的化合物，其具有以下一般公式 Q-L1-P-L2-M-X-L3-A 其中变量Q、L1、P、L2、M、X、L3和A的定义在此处提供。本发明还提供了用于这些化合物的组合物和方法，例如，用于治疗2型糖尿病。
• [EN] 2,4'-BIPYRIDINYL COMPOUNDS AS PROTEIN KINASE D INHIBITORS USEFUL FOR THE TREATMENT OF IA HEART FAILURE AND CANCER<br/>[FR] COMPOSÉS DE 2,4'-BIPYRIDINYLE COMME INHIBITEURS DE LA PROTÉINE KINASE D UTILES POUR LE TRAITEMENT DE L'INSUFFISANCE CARDIAQUE ET DU CANCER
  申请人：NOVARTIS AG

  公开号：WO2009150230A1

  公开（公告）日：2009-12-17

  The present invention provides novel organic compounds of Formula I: methods of use, and pharmaceutical compositions thereof.

  本发明提供了式I的新型有机化合物：其使用方法和药物组合物。
• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES QUI LUI SONT ASSOCIÉS
  申请人：ARENA PHARM INC

  公开号：WO2012135570A1

  公开（公告）日：2012-10-04

  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 pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, 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)化合物以及药用可接受的盐、溶剂化物和水合物，它们作为单一药剂或与一个或多个药物制剂如DPP-IV抑制剂、双胍类药物或α-葡萄糖苷酶抑制剂联合使用，在例如治疗以下疾病中有用：GPR119受体相关疾病；通过增加血液中肠促胰岛素水平而改善的状况；代谢相关疾病；2型糖尿病；肥胖；及其相关并发症。
• SUBSTITUTED CARBAMOYLCYCLOALKYL ACETIC ACID DERIVATIVES AS NEP
  申请人：KARKI Rajeshri Ganesh

  公开号：US20120122764A1

  公开（公告）日：2012-05-17

  The present invention provides a compound of formula I; or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , B, X, m and n are defined herein. The invention also relates to a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides pharmaceutical composition of compounds of the invention, and a combination of pharmacologically active agents and a compound of the invention.

  本发明提供了一种具有化学式I的化合物； 或其药学上可接受的盐，其中R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，B，X，m和n在此处被定义。该发明还涉及制造该发明化合物的方法及其治疗用途。本发明进一步提供了该发明化合物的药物组合物，以及具有药理活性剂和该发明化合物的组合。