α-isocyanato-L-O-methyltyrosine methyl ester | 52177-38-5

• 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: α-isocyanato-L-O-methyltyrosine methyl ester
• 英文别名: α-isocyanato-O-methyltyrosine methyl ester；2-Isocyanato-3-(p-methoxyphenyl)propionsaeuremethylester；methyl (2S)-2-isocyanato-3-(4-methoxyphenyl)propanoate
• CAS: 52177-38-5
• 化学式: C₁₂H₁₃NO₄
• 分子量: 235.24
• InChiKey: JTBBIWAQEQIHSU-NSHDSACASA-N

物化性质

• 沸点：
  335.7±37.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  65
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  α-isocyanato-L-O-methyltyrosine methyl ester 在 lithium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.5h， 生成 (2RS)-<<(2,3-dihydroxypropyl)methylamino>carbonyl>-O-methyltyrosine
  参考文献：
  名称：

  Water-soluble renin inhibitors: design of a subnanomolar inhibitor with a prolonged duration of action

  摘要：

  Incorporation of nonreactive polar functionalities at the C- and N-termini of renin inhibitors led to the development of a subnanomolar compound (21) with millimolar solubility. This inhibitor demonstrated excellent efficacy and a long duration of action upon intravenous administration to monkeys. While activity was also observed intraduodenally, a comparison of the blood pressure responses indicated low bioavailability. Subsequent experiments in rats showed that, although the compound was absorbed from the gastrointestinal tract, extensive liver extraction severely limited bioavailability.

  DOI：

  10.1021/jm00169a024
• 作为产物：
  描述：

  光气 、 O-甲基-L-酪氨酸甲酯 在 吡啶 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 2.0h， 生成 α-isocyanato-L-O-methyltyrosine methyl ester
  参考文献：
  名称：

  Synthesis of a Series of Stromelysin-Selective Thiadiazole Urea Matrix Metalloproteinase Inhibitors

  摘要：

  The synthesis and enzyme inhibition data for a series of thiadiazole urea matrix metalloproteinase (MMP) inhibitors are described. A broad screening effort was utilized to identify several thiadiazoles which were weak inhibitors of stromelysin. Optimization of the thiadiazole leads to include an alpha-amino acid side chain with variable terminal amide substituents provided a series of ureas which were moderately effective stromelysin inhibitors, with K-i's between 0.3 and 1.0 mu M. The most effective analogues utilized an L-phenylalanine as the amino acid component. In particular, unsubstituted 46 had a K-i of 710 nM, while the p-fluoro analogue 52 displayed increased potency (100 nM). Stromelysin inhibition was further improved using a pentafluorophenylalanine substituent which resulted in 70, a 14 nM inhibitor. While gelatinase inhibition was generally poor, the use of 1-(2-pyridyl)piperazine as the amide component usually provided for enhanced activity, with 71 inhibiting gelatinase with a K-i of 770 nM. The combination of this heterocycle with a p-fluorophenylalanine substituent provided the only analogue, 69, with collagenase activity (13 mu M). The SAR for analogues described within this series can be rationalized through consideration of the X-ray structure recently attained for 70 complexed to stromelysin. Uniquely, this structure showed the inhibitor to be completely orientated on the left side of the enzyme cleft. These results suggest that thiadiazole urea heterocycles which incorporate a substituted phenylalanine can provide selective inhibitors of stromelysin. Careful selection of the amide substituent can also provide for analogues with modest gelatinase inhibition.

  DOI：

  10.1021/jm9803222

文献信息

• Renin inhibitors. Dipeptide analogs of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability
  作者：Jacob J. Plattner、Patrick A. Marcotte、Hollis D. Kleinert、Herman H. Stein、Jonathan Greer、Giorgio Bolis、Anthony K. L. Fung、Barbara A. Bopp、Jay R. Luly

  DOI：10.1021/jm00120a006

  日期：1988.12

  A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine residue, compounds with varying degrees of renin inhibitory potency and chymotrypsin susceptibility were obtained. Selected analogues from this group were examined in vivo for both their hypotensive effects and metabolic patterns.
• Edwards,P.D. et al., Journal of the Chemical Society. Perkin transactions I, 1973, p. 2397 - 2402
  作者：Edwards,P.D. et al.

  DOI：——

  日期：——
• Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides
  作者：Saul H. Rosenberg、Kenneth P. Spina、Keith W. Woods、Jim Polakowski、Donald L. Martin、Zhengli Yao、Herman H. Stein、Jerome Cohen、Jennifer L. Barlow

  DOI：10.1021/jm00056a005

  日期：1993.2

  A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.
• ROSENBERG, SAUL H.;WOODS, KEITH W.;SHAM, HING L.;KLEINERT, HOLLIS D.;MART+, J. MED. CHEM., 33,(1990) N, C. 1962-1969
  作者：ROSENBERG, SAUL H.、WOODS, KEITH W.、SHAM, HING L.、KLEINERT, HOLLIS D.、MART+

  DOI：——

  日期：——
• Synthesis of a Series of Stromelysin-Selective Thiadiazole Urea Matrix Metalloproteinase Inhibitors
  作者：E. Jon Jacobsen、Mark A. Mitchell、Susan K. Hendges、Kenneth L. Belonga、Louis L. Skaletzky、Lindsay S. Stelzer、Thomas. J. Lindberg、Edward L. Fritzen、Heinrich J. Schostarez、Theresa J. O'Sullivan、Linda L. Maggiora、Christopher W. Stuchly、Alice L. Laborde、Marc F. Kubicek、Roger A. Poorman、Joan M. Beck、Henry R. Miller、Gary L. Petzold、Pam S. Scott、Scott E. Truesdell、Tanya L. Wallace、John W. Wilks、Christopher Fisher、Linda V. Goodman、Paul S. Kaytes、Stephen R. Ledbetter、Elaine A. Powers、Gabriel Vogeli、John E. Mott、Catherine M. Trepod、Douglas J. Staples、Eric T. Baldwin、Barry C. Finzel

  DOI：10.1021/jm9803222

  日期：1999.5.1

  The synthesis and enzyme inhibition data for a series of thiadiazole urea matrix metalloproteinase (MMP) inhibitors are described. A broad screening effort was utilized to identify several thiadiazoles which were weak inhibitors of stromelysin. Optimization of the thiadiazole leads to include an alpha-amino acid side chain with variable terminal amide substituents provided a series of ureas which were moderately effective stromelysin inhibitors, with K-i's between 0.3 and 1.0 mu M. The most effective analogues utilized an L-phenylalanine as the amino acid component. In particular, unsubstituted 46 had a K-i of 710 nM, while the p-fluoro analogue 52 displayed increased potency (100 nM). Stromelysin inhibition was further improved using a pentafluorophenylalanine substituent which resulted in 70, a 14 nM inhibitor. While gelatinase inhibition was generally poor, the use of 1-(2-pyridyl)piperazine as the amide component usually provided for enhanced activity, with 71 inhibiting gelatinase with a K-i of 770 nM. The combination of this heterocycle with a p-fluorophenylalanine substituent provided the only analogue, 69, with collagenase activity (13 mu M). The SAR for analogues described within this series can be rationalized through consideration of the X-ray structure recently attained for 70 complexed to stromelysin. Uniquely, this structure showed the inhibitor to be completely orientated on the left side of the enzyme cleft. These results suggest that thiadiazole urea heterocycles which incorporate a substituted phenylalanine can provide selective inhibitors of stromelysin. Careful selection of the amide substituent can also provide for analogues with modest gelatinase inhibition.