(3R)-2-[(4-methoxyphenyl)-(3,3,3-trifluoropropoxy)phosphoryl]-N-phenylmethoxy-3,4-dihydro-1H-isoquinoline-3-carboxamide | 1026438-73-2

• 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: (3R)-2-[(4-methoxyphenyl)-(3,3,3-trifluoropropoxy)phosphoryl]-N-phenylmethoxy-3,4-dihydro-1H-isoquinoline-3-carboxamide
• CAS: 1026438-73-2
• 化学式: C₂₇H₂₈F₃N₂O₅P
• 分子量: 548.499
• InChiKey: NGQWUXXCMIDYOX-PNRFPLAFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  77.1
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (3R)-2-[(4-methoxyphenyl)-(3,3,3-trifluoropropoxy)phosphoryl]-N-phenylmethoxy-3,4-dihydro-1H-isoquinoline-3-carboxamide 在 10percent Pd/C 氢气 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以35%的产率得到(3R)-N-hydroxy-2-[(R)-(3,3,3-trifluoropropoxy)(4-methoxyphenyl)phosphoryl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
  参考文献：
  名称：

  New Strategy for Antedrug Application:  Development of Metalloproteinase Inhibitors as Antipsoriatic Drugs

  摘要：

  Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and lieparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.

  DOI：

  10.1021/jm010349c
• 作为产物：
  描述：

  (3R)-N-benzyloxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 在 吡啶 作用下， 反应 0.25h， 生成 (3R)-2-[(4-methoxyphenyl)-(3,3,3-trifluoropropoxy)phosphoryl]-N-phenylmethoxy-3,4-dihydro-1H-isoquinoline-3-carboxamide
  参考文献：
  名称：

  New Strategy for Antedrug Application:  Development of Metalloproteinase Inhibitors as Antipsoriatic Drugs

  摘要：

  Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and lieparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.

  DOI：

  10.1021/jm010349c

文献信息

• Encounter with Unexpected Collagenase-1 Selective Inhibitor: Switchover of Inhibitor Binding Pocket Induced by Fluorine Atom
  作者：Masaaki Sawa、Hirosato Kondo、Shin-ichiro Nishimura

  DOI：10.1016/s0960-894x(01)00796-x

  日期：2002.2

  Phosphonamide-based inhibitors having trifluoromethyl moiety showed highly selective inhibition against MMP-1. A possible mechanism of the selectivity of MMP-1 inhibitors through the switchover of the binding pocket was speculated by computational calculations. As a consequence of the unexpected selectivity, the specific interaction of CF3 group of the inhibitor and Arg214 in the S1' pocket of MMP-1 conducted a low binding energy. (C) 2002 Elsevier Science Ltd. All rights reserved.