D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NMch-Arg

• 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: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NMch-Arg
• 英文别名: H-D-Arg-Arg-Pro-Hyp-Gly-2Thi-Ser-D-Tic-N(CH2cHex)Gly-Arg-OH；(2S)-2-[[2-[[(3R)-2-[(2S)-2-[[(2S)-2-[[2-[[(2S,4R)-1-[(2S)-1-[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-(cyclohexylmethyl)amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoic acid
• 化学式: C₅₉H₉₁N₁₉O₁₃S
• 分子量: 1306.56
• InChiKey: BFUVWSMFTLHCHD-CCWXVQQGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.9
• 重原子数：
  92
• 可旋转键数：
  33
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  552
• 氢给体数：
  15
• 氢受体数：
  18

反应信息

• 作为产物：
  描述：

  N-叔丁氧羰基-N'-甲苯磺酰基-L-精氨酸 、 N-BOC-O-苄基-L-丝氨酸 、 1,1-dimethylethyl N-(carboxymethyl)-N-(cyclohexylmethyl)carbamate 、 BOC-D-1,2,3,4-四氢异喹啉-3-羧酸 、 alkaline earth salt of/the/ methylsulfuric acid 生成 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NMch-Arg
  参考文献：
  名称：

  Bradykinin Receptor Antagonists Containing N-Substituted Amino Acids:  In Vitro and in Vivo B₂ and B₁ Receptor Antagonist Activity

  摘要：

  We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B-2) receptor for antagonist activity by incorporating N-Alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)- D-Tic(7)-N-Chg(8)-Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) Bz receptor antagonist devoid of in vitro B-1 antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B-2 antagonist activity. Although devoid of activity in a classic B-1 isolated tissue assay, B-1 antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK1 receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B-2 pA(2) = 9.1). Antagonist 13 (Hyp(2), NChg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human Bz receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action.

  DOI：

  10.1021/jm950716i

文献信息

• Bradykinin Receptor Antagonists Containing N-Substituted Amino Acids:  <i>In Vitro</i> and <i>in Vivo</i> B₂ and B₁ Receptor Antagonist Activity
  作者：Val S. Goodfellow、Manoj V. Marathe、Karen G. Kuhlman、Timothy D. Fitzpatrick、David Cuadrado、Wendy Hanson、John S. Zuzack、Sherman E. Ross、Maciej Wieczorek、Michael Burkard、Eric T. Whalley

  DOI：10.1021/jm950716i

  日期：1996.1.1

  We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B-2) receptor for antagonist activity by incorporating N-Alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)- D-Tic(7)-N-Chg(8)-Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) Bz receptor antagonist devoid of in vitro B-1 antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B-2 antagonist activity. Although devoid of activity in a classic B-1 isolated tissue assay, B-1 antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK1 receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B-2 pA(2) = 9.1). Antagonist 13 (Hyp(2), NChg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human Bz receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action.