(3S)-3-hydroxy-(4S)-4-<(tert-butyloxycarbonyl)amino>-5-cyclohexylpentanoic acid ethyl ester | 98105-43-2

• 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: (3S)-3-hydroxy-(4S)-4-<(tert-butyloxycarbonyl)amino>-5-cyclohexylpentanoic acid ethyl ester
• 英文别名: ethyl (3S,4S)-4-<(tert-butyloxycarbonyl)amino>-5-cyclohexyl-3-hydroxypentanoate；ethyl (3S,4S)-4-<(tert-butoxycarbonyl)amino>-5-cyclohexyl-3-hydroxypentanoate；ethyl N-tert-butoxycarbonyl-(3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate；N-Boc-(3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester；Ethyl N-Boc-(3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate；ethyl (3S,4S)-4-[(tert-butoxycarbonyl)amino]-5-cyclohexyl-3-hydroxypentanoate；ethyl (3S,4S)-5-cyclohexyl-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate
• CAS: 98105-43-2
• 化学式: C₁₈H₃₃NO₅
• 分子量: 343.464
• InChiKey: WDSXRCWSAYWNFK-GJZGRUSLSA-N

物化性质

• 熔点：
  67-69 °C
• 沸点：
  479.4±35.0 °C(Predicted)
• 密度：
  1.062±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S)-3-hydroxy-(4S)-4-<(tert-butyloxycarbonyl)amino>-5-cyclohexylpentanoic acid ethyl ester 在 2-氨甲基吡啶 、 1-羟基苯并三唑 、 1-羟基苯并三唑一水物 、 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 18.0h， 生成 tert-butyl N-[(2S,3S)-1-cyclohexyl-3-hydroxy-5-[[(2S)-4-methyl-1-oxo-1-[[3-(phenylmethoxycarbonylaminomethyl)phenyl]methylamino]pentan-2-yl]amino]-5-oxopentan-2-yl]carbamate
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

  摘要：

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.

  DOI：

  10.1021/jm00171a005
• 作为产物：
  描述：

  丁氧羰基--环乙基-丙氨酸-羟基盐酸盐 在 sodium cyanoborohydride 、 溶剂黄146 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 39.5h， 生成 (3S)-3-hydroxy-(4S)-4-<(tert-butyloxycarbonyl)amino>-5-cyclohexylpentanoic acid ethyl ester
  参考文献：
  名称：

  A short and efficient synthesis of (3S,4S)-4-[(tert-Butyloxycarbonyl)amino]-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester

  摘要：

  DOI：

  10.1021/jo00239a036

文献信息

• Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analog inhibitors containing a novel analog of statine
  作者：Joshua Boger、Linda S. Payne、Debra S. Perlow、Nancy S. Lohr、Martin Poe、Edward H. Blaine、Edgar H. Ulm、Terry W. Schorn、Bruce I. LaMont

  DOI：10.1021/jm00150a007

  日期：1985.12

  Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin. Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic

  合成了肾素八肽底物的类似物，其中用（3S，4S）-4-氨基-3-羟基-6-甲基庚酸（statine，Sta）取代易裂二肽将底物序列转变为有效的过渡态类似物，肾素的竞争性抑制剂。Sta的环己基丙氨酰基类似物（3S，4S）-4-氨基-5-环己基-3-羟基戊酸（ACHPA）的合成和掺入提供了迄今为止报道的最有效的肾素抑制剂，包括N-异戊基-L-组氨酸-L-脯氨酰基-L-苯丙氨酰基-L-组氨酸-ACHPA-L-亮氨酰-L-苯丙氨酰胺[Iva-His-Pro-Phe-His-ACHPA-Leu-Phe-NH2,3]，肾素抑制Ki = 1.6 X 10（-10）M（人肾素），IC50 = 1.7 X 10（-10）M（人血浆肾素），IC50 = 1.9 X 10（-9）M（犬血浆肾素）和IC50 = 2.1 X 10（-8）M（大鼠血浆肾素）。含有ACHPA的这种抑制剂3，与人肾素的效价比含Sta的抑
• 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。
• Synthesis of statine and its analogues by homogeneous asymmetric hydrogenation
  作者：T. Nishi、M. Kitamura、T. Ohkuma、R. Noyori

  DOI：10.1016/s0040-4039(00)82338-2

  日期：1988.1

  Diastereoselective hydrogenation of N-protected γ-amino β-keto esters catalyzed by BINAP--Ru(II) complexes provides an efficient entry to the statine series with high enantiomeric purities.

  BINAP-Ru（II）配合物催化的N保护的γ-氨基β-酮酯的非对映选择性氢化为高纯度对映体系列提供了有效途径。
• New Renin Inhibitors Containing Pseudodipeptidic Units in P3-P2 and P1-P1' Positions
  作者：Ryszard Paruszewski、Paweł Jaworski、Magdalena Bodnar、Jadwiga Dudkiewicz-Wilczyńska、Iza Roman

  DOI：10.1248/cpb.53.1305

  日期：——

  A series of four non-peptidic renin inhibitors have been designed and synthesized. All of them contain in their molecule (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), a hydrophobic portion at the C-terminus and a second dipeptide-like transition state analog or unnatural dipeptidic fragment at the N-terminus. Inhibitory activity of the compounds was measured in vitro by high performance liquid chromatography (HPLC). Their IC50 (M/l) values were: <10−3 (12), 1.0×10−6 (19), 4.0×10−4 (23) and 1.0×10−6 (29), respectively. All the compounds are stable against chymotrypsin.

  我们设计并合成了一系列四种非肽类肾素抑制剂。它们的分子中都含有(3S,4S)-4-氨基-5-环己基-3-羟基戊酸（ACHPA），C-端为疏水部分，N-端为第二个二肽样过渡态类似物或非天然二肽片段。这些化合物的抑制活性是通过高效液相色谱法（HPLC）在体外测定的。它们的 IC50（<小>M/升）值分别为分别为 <10-3 (12)、1.0×10-6 (19)、4.0×10-4 (23) 和 1.0×10-6 (29)。所有化合物对糜蛋白酶都很稳定。
• Winiecka, Iwona; Dudkiewicz-Wilczynska, Jadwiga; Roman, Iza, Acta poloniae pharmaceutica, 2010, vol. 67, # 4, p. 367 - 374
  作者：Winiecka, Iwona、Dudkiewicz-Wilczynska, Jadwiga、Roman, Iza、Paruszewski, Ryszard

  DOI：——

  日期：——