(S)-3-(4-Fluoro-phenyl)-N-methyl-2-[3-(5-thioxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-ureido]-propionamide | 198700-82-2

• 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: (S)-3-(4-Fluoro-phenyl)-N-methyl-2-[3-(5-thioxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-ureido]-propionamide
• 英文别名: (2S)-3-(4-fluorophenyl)-N-methyl-2-[(2-sulfanylidene-3H-1,3,4-thiadiazol-5-yl)carbamoylamino]propanamide
• CAS: 198700-82-2
• 化学式: C₁₃H₁₄FN₅O₂S₂
• 分子量: 355.417
• InChiKey: GYHXBKOKZOVYIA-VIFPVBQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  152
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(2-吡啶基)哌嗪 、 (S)-3-(4-Fluoro-phenyl)-N-methyl-2-[3-(5-thioxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-ureido]-propionamide 以 乙醇 为溶剂， 反应 72.0h， 以55%的产率得到(S)-1-[2-[[[(4,5-Dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]amino]-1-oxo-3-(4-fluorophenyl)propyl]-4-(2-pyridinyl)piperazine
  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
• 作为产物：
  描述：

  H-4-fluoro-L-Phe-OMe 在 吡啶 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 91.0h， 生成 (S)-3-(4-Fluoro-phenyl)-N-methyl-2-[3-(5-thioxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-ureido]-propionamide
  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

• [EN] THIADIAZOLYL(THIO)UREAS USEFUL AS MATRIX METALLOPROTEASE INHIBITORS<br/>[FR] THIADIAZOLYL(THIO)UREES UTILES COMME INHIBITEURS DE METALLOPROTEASES A MATRICE
  申请人：PHARMACIA & UPJOHN COMPANY

  公开号：WO1997040031A1

  公开（公告）日：1997-10-30

  (EN) The present invention provides novel thiadiazole derivatives represented by formula (I) or pharmaceutical acceptable salts thereof wherein the compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysins, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to connective tissue degradation.(FR) Nouveaux dérivés de thiadiazole de formule (I), ou leurs sels pharmaceutiquement acceptables. Les composés décrits inhibent différents enzymes de la famille des métalloprotéinases à matrices, essentiellement les stromélysines, et sont de ce fait utiles dans le traitement des maladies liées à l'activité des métalloendoprotéinases à matrice, telles que l'arthrose, la polyarthrite rhumatoïde, l'arthrite aiguë suppurée, les ostéopénies telles que l'ostéoporose, la métastase des tumeurs (invasion et croissance), la périodontite, la gingivite, l'ulcère de la cornée, l'ulcère dermique, l'ulcère gastrique et d'autres maladies liées à la dégradation du tissu conjonctif.

  （中文翻译）本发明提供了新的硫代氮唑衍生物，其化学式为(I)，或其药学上可接受的盐，其中本发明的化合物抑制基质金属蛋白酶家族中的各种酶，主要是溶解酶，因此在治疗基质金属内切蛋白酶疾病（如骨关节炎、类风湿性关节炎、化脓性关节炎、骨质疏松症如骨质疏松症、肿瘤转移（侵袭和生长）、牙周炎、牙龈炎、角膜溃疡、皮肤溃疡、胃溃疡和其他与结缔组织降解相关的疾病方面有用。
• THIADIAZOLYL(THIO)UREAS USEFUL AS MATRIX METALLOPROTEASE INHIBITORS
  申请人：PHARMACIA & UPJOHN COMPANY

  公开号：EP0900211B1

  公开（公告）日：2003-07-02
• 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.