4-Benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenyl-pentanamide | 130405-01-5

• 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: 4-Benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenyl-pentanamide
• 英文别名: benzyl N-(5-amino-4,4-difluoro-3-hydroxy-5-oxo-1-phenylpentan-2-yl)carbamate
• CAS: 130405-01-5
• 化学式: C₁₉H₂₀F₂N₂O₄
• 分子量: 378.376
• InChiKey: CQHOZRYMWZICSN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-Benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenyl-pentanamide 在 10percent Pd/C N-乙基吗啉 、 盐酸 、 氢气 、 戴斯-马丁氧化剂 、 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 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 45.0h， 生成 {1-[(1-Benzyl-3-carbamoyl-3,3-difluoro-2-oxo-propylcarbamoyl)-methyl]-6-oxo-2-m-tolyl-1,6-dihydro-pyrimidin-5-yl}-carbamic acid benzyl ester
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase

  摘要：

  Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P-3-P-2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K-i of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

  DOI：

  10.1021/jm000497n
• 作为产物：
  描述：

  4-benzyl-4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxybutanoic acid 在 氨 、 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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 4-Benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenyl-pentanamide
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase

  摘要：

  Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P-3-P-2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K-i of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

  DOI：

  10.1021/jm000497n

文献信息

• Novel peptidase inhibitors
  申请人：MERRELL DOW PHARMACEUTICALS INC.

  公开号：EP0356595A1

  公开（公告）日：1990-03-07

  This invention relates to analogs of peptidase substrates in which the nitrogen atom of the scissile amide bond of a partial retropeptide analog of the substrate has been replaced by a difluoromethylene moiety. These peptidase substrate analogs provide specific enzyme inhibitors for a variety of proteases, the inhibition of which exert valuable pharmacological activities and therefore have useful physiological consequences in a variety of disease states.

  这项发明涉及肽酶底物的类似物，其中底物的部分反肽类似物的可切割酰胺键的氮原子被二氟甲亚甲基取代。这些肽酶底物类似物提供了各种蛋白酶的特异性酶抑制剂，这些蛋白酶的抑制对多种蛋白酶具有有用的药理活性，因此在多种疾病状态下具有有用的生理后果。
• SCHIRLIN, D.;BALTZER, S.;ALTENBERGER, J. M., TETRAHEDRON LETT., 29,(1988) N 30, C. 3687-3690
  作者：SCHIRLIN, D.、BALTZER, S.、ALTENBERGER, J. M.

  DOI：——

  日期：——
• US5114927A
  申请人：——

  公开号：US5114927A

  公开（公告）日：1992-05-19
• Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase
  作者：Fumihiko Akahoshi、Atsuyuki Ashimori、Hiroshi Sakashita、Takuya Yoshimura、Masahiro Eda、Teruaki Imada、Masahide Nakajima、Naoko Mitsutomi、Shigeki Kuwahara、Tatsuyuki Ohtsuka、Chikara Fukaya、Mizuo Miyazaki、Norifumi Nakamura

  DOI：10.1021/jm000497n

  日期：2001.4.1

  Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P-3-P-2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K-i of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.