(R)-N⁴-Benzyloxy-N¹-((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2-isobutyl-succinamide | 145337-54-8

• 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: (R)-N⁴-Benzyloxy-N¹-((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2-isobutyl-succinamide
• 英文别名: (2R)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-2-(2-methylpropyl)-N'-phenylmethoxybutanediamide
• CAS: 145337-54-8
• 化学式: C₂₂H₃₅N₃O₄
• 分子量: 405.538
• InChiKey: GXAUSLPWXIPAIY-IEBWSBKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  96.5
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-N⁴-Benzyloxy-N¹-((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2-isobutyl-succinamide 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 生成 (2R)-N1-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N4-hydroxy-2-(2-methylpropyl)-butanediamide
  参考文献：
  名称：

  Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors:  An Examination of the Subsite Pocket

  摘要：

  The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (Delta MT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an a-branched alkyl group is critical for the binding toward Delta MT1, while the introduction of a bulky group at the a-position of hydroxamic acid seems to diminish the activity against Delta MT1. Summation of the data on the sensitivity of Delta MT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of Delta MT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against Delta MT1 over MMP-1, but no selectivity between Delta MT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.

  DOI：

  10.1021/jm970404a
• 作为产物：
  描述：

  2-(tert-butoxycarbonyl)-(3R)-3-isobutylsuccinic acid 在 N-甲基吗啉 、 三氟甲磺酸三甲基硅酯 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 生成 (R)-N⁴-Benzyloxy-N¹-((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2-isobutyl-succinamide
  参考文献：
  名称：

  Design and synthesis of the cartilage protective agent (CPA, Ro32-3555)

  摘要：

  A novel series of MMP inhibitors has been identified. The compounds are potent selective inhibitors of collagenase with good solubility and oral bioavailability. One compound, designated Ro32-3555, has been selected for development as a cartilage protective agent for use in the treatment of rheumatoid-and osteoarthritis. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0960-894x(97)00416-2

文献信息

• Amino acid derivatives
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0497192A2

  公开（公告）日：1992-08-05

  The invention provides compounds of the formula wherein A represents the group R1 represents hydrogen, amino, protected amino, acylamino or lower alkyl optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-lH-benz[d,e]isoquinol-2-yl, carboxy, protected carboxy, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino; R2 represents hydrogen or lower alkyl optionally substituted by aryl, amino, protected amino, di(lower alkyl)- amino, guanidino, carboxyl, protected carboxyl, carbamoyl, mono(lower alkyl) carbamoyl, di(lower alkyl)-carbamoyl, di(lower alkoxy)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino; R3 represents hydrogen or lower alkyl optionally substituted by hydroxy, protected hydroxy, amino or protected amino; R4 represents hydrogen, hydroxy, lower alkoxy or benzyloxy; and R5 represents hydrogen or halogen and their pharmaceutically acceptable salts. These compounds are useful for the control or prevention of degenerative joint diseases or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured according to known methods.

  本发明提供了式中化合物 其中 A 代表基团 R1代表氢、氨基、受保护氨基、酰氨基或任选被芳基取代的低级烷基、羟基、受保护羟基、氨基、受保护氨基、酰氨基、马来酰亚胺基、琥珀酰亚胺基、萘酰亚胺基、2、3-二氢-1,3-二氧代-lH-苯并[d,e]异喹啉-2-基、羧基、受保护的羧基、氨基甲酰基、单（低级烷基）氨基甲酰基、二（低级烷基）氨基甲酰基、二（低级烷基）氨基、羧基-低级烷酰氨基、吡咯烷基或吗啉基；R2 代表氢或被芳基、氨基、受保护氨基、二（低级烷基）-氨基、胍基、羧基、受保护羧基、氨基甲酰基、单（低级烷基）氨基甲酰基、二（低级烷基）-氨基甲酰基、二（低级烷氧基）膦酰基、二羟基膦酰基、吡咯烷基、哌啶基或吗啉基任选取代的低级烷基；R3 代表氢或任选被羟基、受保护羟基、氨基或受保护氨基取代的低级烷基；R4 代表氢、羟基、低级烷氧基或苄氧基；R5 代表氢或卤素及其药学上可接受的盐类。这些化合物可用于控制或预防退行性关节疾病，或治疗侵袭性肿瘤、动脉粥样硬化或多发性硬化症。它们可以按照已知的方法制造。
• Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors:  An Examination of the Subsite Pocket
  作者：Minoru Yamamoto、Hideki Tsujishita、Noriyuki Hori、Yuichi Ohishi、Shintaro Inoue、Shoji Ikeda、Yasunori Okada

  DOI：10.1021/jm970404a

  日期：1998.4.1

  The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (Delta MT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an a-branched alkyl group is critical for the binding toward Delta MT1, while the introduction of a bulky group at the a-position of hydroxamic acid seems to diminish the activity against Delta MT1. Summation of the data on the sensitivity of Delta MT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of Delta MT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against Delta MT1 over MMP-1, but no selectivity between Delta MT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
• Design and synthesis of the cartilage protective agent (CPA, Ro32-3555)
  作者：M.J. Broadhurst、P.A. Brown、G. Lawton、N. Ballantyne、N. Borkakoti、K.M.K. Bottomley、M.I. Cooper、A.J. Eatherton、I.R. Kilford、P.J. Malsher、J.S. Nixon、E.J. Lewis、B.M. Sutton、W.H. Johnson

  DOI：10.1016/s0960-894x(97)00416-2

  日期：1997.9

  A novel series of MMP inhibitors has been identified. The compounds are potent selective inhibitors of collagenase with good solubility and oral bioavailability. One compound, designated Ro32-3555, has been selected for development as a cartilage protective agent for use in the treatment of rheumatoid-and osteoarthritis. (C) 1997 Elsevier Science Ltd.