Cbz-Lys(Boc)Ψ[CHOHCO]-OMe | 190905-65-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Cbz-Lys(Boc)Ψ[CHOHCO]-OMe
• 英文别名: methyl (3S)-2-hydroxy-7-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(phenylmethoxycarbonylamino)heptanoate
• CAS: 190905-65-8
• 化学式: C₂₁H₃₂N₂O₇
• 分子量: 424.494
• InChiKey: NZHJAGGNYCMMST-BHWOMJMDSA-N

物化性质

• 沸点：
  592.3±50.0 °C(Predicted)
• 密度：
  1.168±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  30
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Cbz-Lys(Boc)Ψ[CHOHCO]-OMe 在 10percent Pd/C 盐酸 、 sodium hydroxide 、 氢气 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 Boc-D-Cha-Pro-Lys(Boc)-carboxy
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

  DOI：

  10.1021/jm011110z
• 作为产物：
  描述：

  Nε-Boc-Nα-Cbz-L-赖氨酸 在 盐酸 、 苄基三乙基氯化铵 、 二异丁基氢化铝 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 乙醚 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 Cbz-Lys(Boc)Ψ[CHOHCO]-OMe
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

  DOI：

  10.1021/jm011110z

文献信息

• [EN] CYCLIC KETO-AMIDE COMPOUNDS AS CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF<br/>[FR] COMPOSÉS CÉTO-AMIDES CYCLIQUES UTILISÉS EN TANT QUE MODULATEURS DE LA CALPAÏNE, ET LEURS PROCÉDÉS DE PRODUCTION ET D'UTILISATION
  申请人：BLADE THERAPEUTICS INC

  公开号：WO2017156071A1

  公开（公告）日：2017-09-14

  The present technology relates to cyclic keto-amide compounds of general formulae I to XXXII, compositions and kits thereof as calpain modulators and methods useful for the treatment of various diseases or disorders such as fibrotic disease or cancer which are associated or mediated, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is also applicable to cyclic keto-amide compounds which inhibit myofibroblast differentiation.

  目前的技术涉及一般式I至XXXII的环状酮酰胺化合物，以及作为钙蛋白酶调节剂的组合物和试剂盒，以及用于治疗与钙蛋白酶（如CAPN1、CAPN2和/或CAPN9）相关或介导的各种疾病或紊乱的方法，如纤维化疾病或癌症。目前的技术还适用于抑制肌成纤维细胞分化的环状酮酰胺化合物。
• Practical synthesis of a peptidomimetic thrombin inhibitor
  作者：Serge Wilmouth、Christel Bufferne-Perret、Christine Flouzat、Grégoire Humblot、Christiane Ray、Nadine Simbille

  DOI：10.1016/j.tet.2009.01.078

  日期：2009.3

  Compound 1 is a low molecular weight thrombin inhibitor developed for treatment of deep vein thrombosis and cardiovascular diseases. We herein report our efforts to develop a robust, efficient and reproducible process suitable for large-scale synthesis of compound 1.

  化合物1是开发用于治疗深静脉血栓形成和心血管疾病的低分子量凝血酶抑制剂。我们在此报告了我们为开发适用于大规模合成化合物1的稳健，有效和可重现方法的努力。
• PEPTIDE DERIVATIVES AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS, PROCESSES FOR PREPARATION OF BOTH, AND USE THEREOF
  申请人：TAIHO PHARMACEUTICAL CO., LTD.

  公开号：EP1333024A1

  公开（公告）日：2003-08-06

  The present invention provides a peptide derivative of formula (I) wherein X is -CHOH- or -CO-; R1 and R2 are hydrogen or substituted oxycarbonyl; R3 is substituted oxycarbonyl; R4 is hydroxyl, lower alkoxy, optionally substituted piperazinyl or the like; R5 is a R-group side chain of an α-amino acid optionally protected by a protective group, R6 is hydroxyl, lower alkoxy or the like; m is 0 or 1; and n is an integer of 2 to 6; or a pharmaceutically acceptable salt thereof. The present invention further provides a production process and use thereof.

  本发明提供了一种式(I)的肽衍生物 其中 X 是-CHOH-或-CO-；R1 和 R2 是氢或取代的氧羰基；R3 是取代的氧羰基；R4 是羟基、低级烷氧基、任选取代的哌嗪基或类似物；R5 是任选受保护基团保护的 α-氨基酸的 R 基侧链，R6 是羟基、低级烷氧基或类似物；m 是 0 或 1；n 是 2 至 6 的整数；或其药学上可接受的盐。本发明进一步提供了一种生产工艺及其用途。
• Peptide derivatives and pharmaceutically acceptable salts, thereof, processes for preparation of both, and use thereof
  申请人：——

  公开号：US20030087828A1

  公开（公告）日：2003-05-08

  The present invention provides a peptide derivative of formula (I) 1 wherein X is —CHOH— or —CO—; R 1 and R 2 are hydrogen or substituted oxycarbonyl; R 3 is substituted oxycarbonyl; R 4 is hydroxyl, lower alkoxy, optionally substituted piperazinyl or the like; R 5 is a R-group side chain of an &agr;-amino acid optionally protected by a protective group, R 6 is hydroxyl, lower alkoxy or the like; m is 0 or 1; and n is an integer of 2 to 6; or a pharmaceutically acceptable salt thereof. The present invention further provides a production process and use thereof.

  本发明提供了一种式 (I) 的肽衍生物 1 其中 X 为 -CHOH- 或 -CO-; R 1 和 R 2 是氢或取代的氧羰基 3 是取代的氧羰基 4 是羟基、低级烷氧基、任选取代的哌嗪基或类似物；R 5 是由保护基团任选保护的&agr;-氨基酸的 R 基侧链，R 6 是羟基、低级烷氧基或类似物；m 是 0 或 1；n 是 2 至 6 的整数；或 其药学上可接受的盐。 本发明进一步提供了一种生产工艺及其用途。
• WO2008/97676
  申请人：——

  公开号：——

  公开（公告）日：——