(3S,4R)-3-benzyl-4-{[(4-chlorophenyl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester | 1428269-14-0

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (3S,4R)-3-benzyl-4-{[(4-chlorophenyl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (3S,4R)-3-benzyl-4-[(N-(4-chlorophenyl)anilino)methyl]pyrrolidine-1-carboxylate
• CAS: 1428269-14-0
• 化学式: C₂₉H₃₃ClN₂O₂
• 分子量: 477.046
• InChiKey: MUPZLKUZJXMGQH-RPWUZVMVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3S,4R)-3-benzyl-4-{[(4-chlorophenyl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 4.0h， 以100%的产率得到N-[[(3S,4S)-4-benzylpyrrolidin-3-yl]methyl]-4-chloro-N-phenylaniline;hydrochloride
  参考文献：
  名称：

  The Discovery of Novel Potenttrans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches

  摘要：

  The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3(sp) cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

  DOI：

  10.1021/jm3017078
• 作为产物：
  描述：

  溴苯 、 (3S,4R)-3-benzyl-4-[(4-chlorophenylamino)methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester 在 di-μ-bromobis(tri-tert-butylphosphine)dipalladium(I) 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 反应 0.25h， 以76%的产率得到(3S,4R)-3-benzyl-4-{[(4-chlorophenyl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  The Discovery of Novel Potenttrans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches

  摘要：

  The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3(sp) cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

  DOI：

  10.1021/jm3017078