1-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane | 198903-86-5

• 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: 1-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane
• 英文别名: 2,5,6,10,13-Pentaazatetradecanedioic acid, 8-hydroxy-3,12-bis(1-methylethyl)-4,11-dioxo-9-(phenylmethyl)-6-((4-(5-thiazolyl)phenyl)methyl)-, dimethyl ester, (3S,8S,9S,12S)-；methyl N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]amino]-4-phenylbutyl]-2-[[4-(1,3-thiazol-5-yl)phenyl]methyl]hydrazinyl]-3-methyl-1-oxobutan-2-yl]carbamate
• CAS: 198903-86-5
• 化学式: C₃₄H₄₆N₆O₇S
• 分子量: 682.841
• InChiKey: BCSCPTFLLCLSSZ-ZHTHUIBPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  48
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  200
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane 在 甲酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 反应 12.67h， 生成 1-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane
  参考文献：
  名称：

  New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors:  Candidates for Clinical Development

  摘要：

  On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,(8) azadipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) ororthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.

  DOI：

  10.1021/jm970873c

文献信息

• New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors:  Candidates for Clinical Development
  作者：Guido Bold、Alexander Fässler、Hans-Georg Capraro、Robert Cozens、Thomas Klimkait、Janis Lazdins、Jürgen Mestan、Bernard Poncioni、Johannes Rösel、David Stover、Marina Tintelnot-Blomley、Figan Acemoglu、Werner Beck、Eugen Boss、Martin Eschbach、Thomas Hürlimann、Elvira Masso、Serge Roussel、Katharina Ucci-Stoll、Dominique Wyss、Marc Lang

  DOI：10.1021/jm970873c

  日期：1998.8.1

  On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,(8) azadipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) ororthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.