1H-thieno<3,4-d>imidazol-2(3H)-one, tetrahydro-4-(5-chloropentyl)-, <3aS-(3aα,4β,6aα)>-

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并咪唑类化合物
• 英文名称: 1H-thieno<3,4-d>imidazol-2(3H)-one, tetrahydro-4-(5-chloropentyl)-, <3aS-(3aα,4β,6aα)>-
• 英文别名: 1H-thieno[3,4-d]imidazol-2(3H)-one, tetrahydro-4-(5-chloropentyl)-, (3aS-(3aα,4β,6aα))-；(3aS,4S,6aR)-4-(5-chloropentyl)-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-2-one
• 化学式: C₁₀H₁₇ClN₂OS
• 分子量: 248.777
• InChiKey: PRIKUDQQIRMIEC-CIUDSAMLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  (+)生物素-N-琥珀酰亚胺基酯 在 吡啶 、 sodium tetrahydroborate 、 甲基磺酰氯 作用下， 以 四氢呋喃 、 六甲基磷酰三胺 为溶剂， 反应 7.0h， 生成 1H-thieno<3,4-d>imidazol-2(3H)-one, tetrahydro-4-(5-chloropentyl)-, <3aS-(3aα,4β,6aα)>-
  参考文献：
  名称：

  Evaluation of a vitamin-cloaking strategy for oligopeptide therapeutics: biotinylated HIV-1 protease inhibitors

  摘要：

  The outstanding limitations to the oligopeptide as a therapeutic agent are poor oral availability and rapid biliary clearance. To address these concerns a series of eight peptidic HIV-1 protease inhibitors containing the structural segment of the vitamin biotin have been prepared. These have been evaluated with regard to the hypothesis that this vitamin would cloak the peptidic character of these oligopeptides, and thus impart to these inhibitors the potential for absorption and distribution via biotin transporters and receptors. By iterative optimization about a -Chal psi[CH- (OH)CH(OH)]Val- core inhibitory insert, three particularly potent inhibitors (K-i less than or equal to 10 nM) of the HIV-1 protease were obtained. Although excellent cell culture antiviral activity is observed for other peptidic protease inhibitors of comparable affinity, none in this series exhibited satisfactory antiviral activity. This failure is-attributed to the incompatibility of the hydrophilic and hydrogen-bonding biotin segment, with the facile membrane permeability and intracellular access presumably required for antiviral activity. The ability of the biotin to cloak the peptide, and thus render the overall appearance of the conjugate as that of a vitamin, was evaluated. Four of this series were evaluated for recognition by the Caco-2 cell intestinal biotin transporter, None inhibited competitively biotin uptake, indicating a lack of recognition. A vitamin may bind to a specific protein carrier, and thus attain an improved serum profile (by resistance to biliary clearance) and advantageous delivery to cells. Therefore, the serum concentrations of three were evaluated following an iv bolus in a rat model for serum clearance. One of the three protease inhibitors (L-idonamide, 6-cyclohexyl-2,5,6-trideoxy-2-(1-methylethyl)-5-[[3-methyl-1-oxo-2-[[5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-1-oxopentyl]amino]butyl]amino]-N-[2-methyl-1-[[(2-pyridinylmethyl)amino] carbonyl]butyl]-, [3aS-[3a alpha,4 beta(1R*,2R*;3R*),6a alpha]]-) sustained a more than 5-fold increase in serum concentration at all time points relative to the benchmark structure. The remaining two had serum concentrations at least equal to the benchmark, suggestive of improved resistance to clearance. One(L-idonamide, 6-cyclohexyl-2,5,6-trideoxy-5-[[2-[[5-(hexahydro-2-oxo-1H-thieno-[3,4-d]imidazol-4-yl)pentyl]thio]benzoyl]amino]-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]-, [3aS-[3a alpha,4 beta(1R*,2R*),6a alpha]]-) was prepared as a complex with the biotin-binding protein avidin. Avidin may resemble an endogenous serum biotin carrier protein. The antiviral activity (evaluated in an H9-HTLV(IIIB) acute HIV-1 infection assay) of the inhibitor and the avidin complex was identical. This suggests that the avidin-inhibitor complex is capable of cell internalization. Although the weak antiviral activity of these biotinylated inhibitors precludes consideration as practical HIV therapeutics, the overall data remain suggestive of vitamin cloaking of oligopeptides as a strategy of potential value.

  DOI：

  10.1021/jm00028a013