isopropyl (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate*HCl | 132271-76-2

• 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: isopropyl (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate*HCl
• CAS: 132271-76-2
• 化学式: C₁₄H₂₇NO₃*ClH
• 分子量: 293.834
• InChiKey: ORVFPVNZLMLLSB-QNTKWALQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.41
• 重原子数：
  19.0
• 可旋转键数：
  6.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  72.55
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  isopropyl (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate*HCl 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 (3S,4S)-4-{(S)-2-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-3-[1-(2,4-dinitro-phenyl)-1H-imidazol-4-yl]-propionylamino}-5-cyclohexyl-3-hydroxy-pentanoic acid isopropyl ester
  参考文献：
  名称：

  Renin inhibitors containing new P1-P1' dipeptide mimetics with heterocycles in P1'

  摘要：

  A series of renin inhibitors containing new P1-P1' dipeptide mimetics are presented The P1-P1' mimetics were obtained from (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-[(omega-mesyloxy)alkyl]-2,2-dimethyloxazolidines 5b, 9, and 11b by nucleophilic substitution of the mesylate groups with the sodium salts of mercapto- and hydroxyheterocycles. Removal of the protecting groups and stepwise acylations with amino acid derivatives provided renin inhibitors with a length of a tripeptide. Replacement of P2 histidine by other amino acids maintained or enhanced renin inhibitory potency. By alteration of P3 phenylalanine, compounds with IC50 values in the nanomolar range and stability against chymotrypsin were obtained. Finally, the effect of the C-terminal heterocycle on the renin inhibition was studied. Compound XVII was examined in vivo for its hypotensive effects. In salt-depleted cynomolgus monkeys, XVII inhibited plasma renin activity and lowered blood pressure after oral administration of a dose of 10 mg/kg.

  DOI：

  10.1021/jm00097a010
• 作为产物：
  描述：

  (3S,4S)-4-tert-Butoxycarbonylamino-5-cyclohexyl-3-hydroxy-pentanoic acid isopropyl ester 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 1.0h， 生成 isopropyl (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate*HCl
  参考文献：
  名称：

  Renin inhibitors containing new P1-P1' dipeptide mimetics with heterocycles in P1'

  摘要：

  A series of renin inhibitors containing new P1-P1' dipeptide mimetics are presented The P1-P1' mimetics were obtained from (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-[(omega-mesyloxy)alkyl]-2,2-dimethyloxazolidines 5b, 9, and 11b by nucleophilic substitution of the mesylate groups with the sodium salts of mercapto- and hydroxyheterocycles. Removal of the protecting groups and stepwise acylations with amino acid derivatives provided renin inhibitors with a length of a tripeptide. Replacement of P2 histidine by other amino acids maintained or enhanced renin inhibitory potency. By alteration of P3 phenylalanine, compounds with IC50 values in the nanomolar range and stability against chymotrypsin were obtained. Finally, the effect of the C-terminal heterocycle on the renin inhibition was studied. Compound XVII was examined in vivo for its hypotensive effects. In salt-depleted cynomolgus monkeys, XVII inhibited plasma renin activity and lowered blood pressure after oral administration of a dose of 10 mg/kg.

  DOI：

  10.1021/jm00097a010

文献信息

• Synthesis and structure-activity relationships of human renin inhibitors designed from angiotensinogen transition state.
  作者：Kinji IIZUKA、Tetsuhide KAMIJO、Hiromu HARADA、Kenji AKAHANE、Tetsuhiro KUBOTA、Yasuo ETOH、Iwao SHIMAOKA、Atsushi TSUBAKI、Makoto MURAKAMI、Toshiaki YAMAGUCHI、Akira IYOBE、Hideaki UMEYAMA、Yoshiaki KISO

  DOI：10.1248/cpb.38.2487

  日期：——

  The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1, , P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50=6.0×10-9 M) and pepsin (IC50=3.5×10-7 M) to the same extent as renin (IC50=8.5×10-10 M), and thus was not specific for renin. The reduction of the β-carbonyl group to methylene group in β-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i : IC50=1.1×10-7 M vs. 1 : IC50=2.4 ×10-9 M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.

  描述了基于血管紧张素原过渡态设计的肾素抑制剂的合成及其构效关系。这些抑制剂在P1-P1、P2和P4-P3位点含有修饰的残基。在P1位点，诺斯他酮类似物侧链烷基基团的尺寸减小，降低了化合物的抑制活性。化合物5j在P2位点含有缬氨酸残基而非组氨酸残基，能有效抑制猫hepsin D（IC50=6.0×10⁻⁹ M）和胃蛋白酶（IC50=3.5×10⁻⁷ M），其抑制活性与肾素相当（IC50=8.5×10⁻¹⁰ M），因此并非特异性针对肾素。P4-P3处β-羰基基团减少为亚甲基基团，使其对人肾素的效能下降了约两个数量级（5i: IC50=1.1×10⁻⁷ M vs. 1: IC50=2.4×10⁻⁹ M）。这些结果证实了我们对口服有效的人肾素抑制剂1与人肾素活性位点间相互作用的分析合理性，显示出1与肾素活性位点的适配良好。合成的实验细节也已呈现。