(S)-1-((R)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)pyrrolidine-2-carboxylic acid | 146621-94-5

• 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: (S)-1-((R)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)pyrrolidine-2-carboxylic acid
• 英文别名: N-Boc-Chg-Pro-OMe；1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline；(2S)-1-[(2R)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]pyrrolidine-2-carboxylic acid
• CAS: 146621-94-5
• 化学式: C₁₈H₃₀N₂O₅
• 分子量: 354.447
• InChiKey: GXJFWLZSFRQBML-UONOGXRCSA-N

物化性质

• 沸点：
  556.2±45.0 °C(Predicted)
• 密度：
  1.186±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-1-((R)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)pyrrolidine-2-carboxylic acid 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 Boc-D-cyclohexylglycine-proline-N-(2-hydroxy-5-chlorobenzyl)amide trifluoroacetate
  参考文献：
  名称：

  Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position

  摘要：

  As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

  DOI：

  10.1021/jm9801713
• 作为产物：
  描述：

  (S)-benzyl 1-((R)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)pyrrolidine-2-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 以92%的产率得到(S)-1-((R)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  通过协同作用增强疏水相互作用和氢键强度：凝血酶抑制剂同类的合成，建模和分子动力学模拟。

  摘要：

  通过计算方法准确预测配体与其受体的结合亲和力是基于结构的药物设计的主要挑战之一。这些预测中潜在的重大错误之一是非共价相互作用的配体结合亲和力贡献是可加的共同假设。本文中，我们介绍了从两个单独的凝血酶抑制剂系列中获得的数据，这些凝血酶抑制剂的大小不断增加，并结合在S3口袋中，并带有或不带有与Gly 216氢键键合的相邻胺的疏水侧链。一米的S1'袋-氯苄基部分结合，并且所述第二具有苄脒部分。当相邻氢键存在时，增强的每的结合亲和力2与缺少该氢键的抑制剂相比，S3袋中疏水接触表面的表面张力分别提高了75％和59％。每结合亲和力的这种改进2演示了疏水相互作用和氢键间的协同性。

  DOI：

  10.1021/jm9016416

文献信息

• Thrombin inhibitors
  申请人：——

  公开号：US20040073025A1

  公开（公告）日：2004-04-15

  Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure Formula (I): wherein u is CH or N; Q is 1)—N(R 25 )CH(R 30 )—wherein the nitrogen atom is attached to R 1 , and R 25 and R 30 are independently selected from the group consisting of hydrogen, C 3-6 cycloalkyl, and C 1-6 alkyl, or 2) wherein the nitrogen atom is attached to R 1 , and m is 0, 1, or 2. 1

  本发明的化合物在抑制凝血酶和相关的血栓闭塞方面具有有用的结构式（I），其中u为CH或N；Q为1）-N（R25）CH（R30）-，其中氮原子连接到R1，且R25和R30分别选自氢，C3-6环烷基和C1-6烷基的群组，或2）其中氮原子连接到R1，且m为0，1或2.1。
• Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1
  作者：Koo Lee、Won-Hyuk Jung、Cheol Won Park、Hee Dong Park、Sun Hwa Lee、O Hwan Kwon

  DOI：10.1016/s0960-894x(02)00093-8

  日期：2002.4

  A series of noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at PI was investigated. While the amidrazone and the amine series displayed limited oral absorption, the amidine series demonstrated generally good oral absorption and strong antithrombotic activity; the single-digit picomolar K-i achieved from this series is among the best yet reported. The present work highlights the benzamidine compound 11f (LB30812) that exhibits excellent overall profiles of potency, oral absorption and antithrombotic efficacy. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases
  作者：Sarah E. Poplawski、Jack H. Lai、David G. Sanford、James L. Sudmeier, Wengen Wu、William W. Bachovchin

  DOI：10.1021/jm100972f

  日期：2011.4.14

  Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency > 100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to I. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.
• US7144899B2
  申请人：——

  公开号：US7144899B2

  公开（公告）日：2006-12-05
• [EN] THROMBIN INHIBITORS<br/>[FR] INHIBITEURS DE THROMBINE
  申请人：MERCK & CO INC

  公开号：WO2002064559A2

  公开（公告）日：2002-08-22

  Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure Formula (I): wherein u is CH or N; Q is 1)-N(R?25)CH(R30¿)- wherein the nitrogen atom is attached to R?1, and R25 and R30¿ are independently selected from the group consisting of hydrogen, C¿3-6?cycloalkyl, and C1-6alkyl, or 2) wherein the nitrogen atom is attached to R?1¿, and m is 0, 1, or 2.