替莫普利 | 110221-53-9

• 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
• 中文名称: 替莫普利
• 中文别名: [(2S,6R)-6-[[(S)-1-(乙氧羰基)-3-苯基丙基]氨基]-5-氧代-2-(2-噻吩基)-1,4-硫氮杂卓-4-基]乙酸；；[(2S,6R)-6-[[(S)-1-(乙氧羰基)-3-苯基丙基]氨基]-5-氧代-2-(2-噻吩基)-1,4-硫氮杂卓-4-基]乙酸；替莫普利拉
• 英文名称: Temocaprilat
• 英文别名: [3H]-Temocaprilat；(2S)-2-[[(2S,6R)-4-(carboxymethyl)-5-oxo-2-thiophen-2-yl-1,4-thiazepan-6-yl]amino]-4-phenylbutanoic acid
• CAS: 110221-53-9
• 化学式: C₂₁H₂₄N₂O₅S₂
• 分子量: 448.564
• InChiKey: KZVWEOXAPZXAFB-BQFCYCMXSA-N

物化性质

• 熔点：
  >2300C (dec)
• 比旋光度：
  25D +63.4° (c = 1 in DMF)
• 沸点：
  743.6±60.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  161
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• 储存条件：
  -20°C

制备方法与用途

特莫卡普利特（特莫卡普利二酸）是血管紧张素转换酶(ACE)的抑制剂。研究显示，替莫卡普利特能够减轻高糖对主动脉内皮细胞增殖的抑制作用，在高血压和血管炎症治疗方面具有潜在的应用价值[1][2][3][4]。

反应信息

• 作为产物：
  描述：

  盐酸替莫普利 在 sodium hydroxide 作用下， 反应 16.0h， 以96%的产率得到替莫普利
  参考文献：
  名称：

  Angiotensin-converting enzyme inhibitors. Perhydro-1,4-thiazepin-5-one derivatives

  摘要：

  alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic acids (monoester monoacids) and their dicarboxylic acids having the hydrophobic substituents at the 2- or 3-position of the thiazepinone ring were prepared and assayed for angiotensin-converting enzyme (ACE) inhibitory activity. The dicarboxylic acids having the pseudoequatorial amino groups at the 6-position and the pseudoequatorial hydrophobic substituents at the 2- or 3-position of the chair conformation of the thiazepinone ring had potent in vitro inhibitory activity. The monoester monoacids having the hydrophobic substituents at the 2-position suppressed pressor response to angiotensin I for a longer duration than those having the substituents at the 3-position when administered orally. The structure-activity relationship was studied by conformational energy calculations of the thiazepinone ring.

  DOI：

  10.1021/jm00394a009

文献信息

• Prodrug composition
  申请人：Hilfinger John

  公开号：US20050137141A1

  公开（公告）日：2005-06-23

  A prodrug composition is provided which includes a pharmaceutical species and an amino acid having a covalent bond to the pharmaceutical species. The pharmaceutical species is characterized by bioavailability of 30% or less and a molecular weight in the range of 100-1000 Daltons. The composition is characterized further in that the pharmaceutical species is not acyclovir, ganciclovir, BRL44385, or penciclovir. Also described is an inventive method of delivering a pharmaceutical species to an individual including the step of orally administering an inventive prodrug to an individual. In one embodiment the prodrug includes a pharmaceutical species characterized by bioavailability of 30% or less, wherein the pharmaceutical species has a molecular weight in the range of 100-1000 Daltons. The inventive prodrug is transported from the gastrointestinal lumen by a specific transporter and is enzymatically cleaved to yield the pharmaceutical species, such that the pharmaceutical species is delivered to the individual.

  提供了一种前药组合物，其中包括一种药用物种和与该药用物种具有共价键的氨基酸。该药用物种的生物利用度为30%或更低，分子量在100-1000道尔顿的范围内。该组合物的特征进一步在于，该药用物种不是阿昔洛韦、甘氨鸟苷、BRL44385或者喷昔洛韦。还描述了一种将药用物种传递给个体的创新方法，其中包括口服给个体一种创新前药的步骤。在一个实施例中，前药包括一种生物利用度为30%或更低的药用物种，该药用物种的分子量在100-1000道尔顿的范围内。该创新前药通过特定转运体从胃肠腔转运，并经酶解裂解以产生药用物种，从而将药用物种传递给个体。
• Hydrolytic Profile for Ester- or Amide-linkage by Carboxylesterases pI 5.3 and 4.5 from Human Liver.
  作者：Satomi TAKAI、Ayuka MATSUDA、Yoshiko USAMI、Tetsuo ADACHI、Tadashi SUGIYAMA、Yoshihiro KATAGIRI、Masae TATEMATSU、Kazuyuki HIRANO

  DOI：10.1248/bpb.20.869

  日期：——

  Carboxylesterases (EC 3.1.1.1) from human liver were purified using Q-Sepharose, Sephadex G-150, isoelectrofocusing and Con A-Sepharose. The calculated molecular mass of the pI 5.3 enzyme was 120 kDa and 61 kDa from the results of Sephadex G-150 gel filtration and SDS-polyacrylamide gel electrophoresis (PAGE), respectively, suggesting that this enzyme is a dimer. On the other hand, carboxylesterase pI 4.5, with a molecular mass of 64 kDa, was a monomer. The activities of both enzymes were inhibited by typical serine enzyme inhibitors. Amino acid sequence analysis of the purified enzymes pI 5.3 and 4.5 showed high homology with rabbit carboxylesterase form 1 and 2, respectively. The results also suggested that carboxylesterase pI 5.3 is identical to the deduced amino acid sequence from cDNA for HU1, and that carboxylesterase pI 4.5 is identical to the deduced amino acid sequence from the cDNA registered as human carboxylesterase (hCE-2) in GenBank. We first purified carboxylesterase pI 4.5 and investigated its hydrolytic activity upon various drugs. The two enzymes differed in substrate specificity. Prodrugs of angiotensin-converting enzyme inhibitors, such as delapril and imidapril, were converted to active metabolites by carboxylesterase pI 5.3, but not by carboxylesterase pI 4.5. The hydrolysis velocity of temocapril by carboxylesterase pI 5.3 was 12-fold faster than by carboxylesterase pI 4.5. In contrast, aspirin, oxybutynin and procaine were hydrolyzed by only carboxylesterase pI 4.5. We also found that an amide-linkage in drugs, except for that in aniracetam, was not a good substrate for the two enzymes. Consequently, carboxylesterases pI 5.3 and 4.5 may be involved in the metabolism of various drugs containing an ester-linkage.

  人类肝脏中的羧酸酯酶（EC 3.1.1.1）通过Q-Sepharose、Sephadex G-150、等电聚焦和Con A-Sepharose进行纯化。pI 5.3酶的计算分子量为120 kDa，而通过Sephadex G-150凝胶滤过和SDS-聚丙烯酰胺凝胶电泳（PAGE）得到的结果分别为61 kDa，这表明该酶是二聚体。另一方面，pI 4.5的羧酸酯酶，分子量为64 kDa，是单体。这两种酶的活性均受到典型的丝氨酸酶抑制剂的抑制。纯化的pI 5.3和pI 4.5酶的氨基酸序列分析显示与兔羧酸酯酶1型和2型具有高度同源性。结果还表明，pI 5.3的羧酸酯酶与从cDNA中推导出的HU1的氨基酸序列相同，而pI 4.5的羧酸酯酶与在GenBank中注册的人类羧酸酯酶（hCE-2）的推导氨基酸序列相同。我们首先纯化了pI 4.5的羧酸酯酶，并研究了其对各种药物的水解活性。这两种酶在底物特异性上有所不同。血管紧张素转化酶抑制剂的前药，如德拉普利和伊米达普利，被pI 5.3羧酸酯酶转化为活性代谢物，而pI 4.5羧酸酯酶则无法转化。pI 5.3对肽环的水解速率是pI 4.5的12倍。相反，只有pI 4.5羧酸酯酶能水解阿司匹林、奥昔布宁和普鲁卡因。我们还发现，除阿尼拉西坦外，药物中的酰胺键对这两种酶并不是良好的底物。因此，pI 5.3和pI 4.5的羧酸酯酶可能参与水解含酯键的各种药物的代谢过程。
• Pharmaceutical preparation comprising an active dispersed on a matrix
  申请人：——

  公开号：US20040058896A1

  公开（公告）日：2004-03-25

  The present invention relates to the field of pharmaceutical technology and describes a novel advantageous preparation for an active ingredient. The novel preparation is suitable for producing a large number of pharmaceutical dosage forms. In the new preparation an active ingredient is present essentially uniformly dispersed in an excipient matrix composed of one or more excipients selected from the group of fatty alcohol, triglyceride, partial glyceride and fatty acid ester.

  本发明涉及制药技术领域，描述了一种新的有利的活性成分制备方法。这种新的制备方法适用于生产大量的药物剂型。在这种新的制备方法中，活性成分基本上均匀地分散在由脂肪醇、甘油三酯、部分甘油酯和脂肪酸酯等多种赋形剂中选择的一种或多种赋形剂组成的赋形剂基质中。
• Heteroaromatic pentacyclic compound and medicinal use thereof
  申请人：Ikemoto Tomoyuki

  公开号：US20060122181A1

  公开（公告）日：2006-06-08

  A 5-membered heteroaromatic ring compound represented by the formula [I] wherein V is CH or N; W is S or O; R 1 and R 2 are each H etc.; X is —N(R 4 )—, —O—, —S—, —SO 2 —N(R 5 )—, —CO—N(R 7 )— etc.; L is wherein R 20 , R 21 , R 22 and R 25 are each H etc.; E is aryl or heteroaromatic ring group; R is —COOH etc.; B is aryl etc.; R 3 is H etc.; Y is —C(R 13 )(R 14 )—N(R 12 )—C(R 13 )(R 14 )—O—, —N(R 11 )—, —O— etc.; A is alkylene; and Z is aryl etc., a prodrug thereof and a pharmaceutically acceptable salt thereof. The compound [I] has a superior protein tyrosine phosphatase 1B inhibitory activity and is useful as a therapeutic agent for diabetes, diabetic complications, hyperlipidemia, obesity and the like.

  一种由公式[I]表示的五元杂环芳香环化合物，其中V为CH或N；W为S或O；R1和R2分别为H等；X为—N(R4)—，—O—，—S—，—SO2—N(R5)—，—CO—N(R7)—等；L为其中R20，R21，R22和R25分别为H等的基团；E为芳基或杂环芳香基团；R为—COOH等；B为芳基等；R3为H等；Y为—C(R13)(R14)—N(R12)—C(R13)(R14)—O—，—N(R11)—，—O—等；A为烷基；Z为芳基等，其前药和药学上可接受的盐。该化合物[I]具有优越的蛋白酪氨酸磷酸酶1B抑制活性，并可用作治疗糖尿病、糖尿病并发症、高脂血症、肥胖症等的治疗剂。
• ANTI-GLYCATION AGENTS FOR PREVENTING AGE-, DIABETES-, AND SMOKING-RELATED COMPLICATIONS
  申请人：YEBOAH Faustinus

  公开号：US20080139664A1

  公开（公告）日：2008-06-12

  The invention provides new inhibitors of protein glycation, identified from compound libraries by a high throughput screening assay. The anti-glycation agents so identified are characterized by a variety of chemical structures and are useful for the prevention or treatment of age-, diabetes-, and smoking-related complications, including neuropathy, nephropathy, ocular pathologies, or the loss of mechanical properties of collagenous tissues. Among compounds identified as having the anti-glycation activity, of special interest are epinephrine and its analogs, in particular D-epinephrine and its analogs, which are particularly useful for the prevention or treatment of age-, diabetes-, and smoking-related ocular pathologies.

  该发明提供了新的蛋白质糖基化抑制剂，通过高通量筛选检测从化合物库中确定。所确定的抗糖基化剂具有各种化学结构，并可用于预防或治疗与年龄、糖尿病和吸烟相关的并发症，包括神经病变、肾病、眼部病理或胶原组织机械性能的丧失。在被确定为具有抗糖基化活性的化合物中，特别感兴趣的是肾上腺素及其类似物，特别是D-肾上腺素及其类似物，这些物质特别适用于预防或治疗与年龄、糖尿病和吸烟相关的眼部病理。