(3R,6R,9S)-3-benzyl-9-((S)-sec-butyl)-6,7-dimethyl-1,4,7,10-tetraazacycloheptadec-15-ene-2,5,8-trione | 843639-67-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (3R,6R,9S)-3-benzyl-9-((S)-sec-butyl)-6,7-dimethyl-1,4,7,10-tetraazacycloheptadec-15-ene-2,5,8-trione
• CAS: 843639-67-8
• 化学式: C₂₆H₄₀N₄O₃
• 分子量: 456.629
• InChiKey: QZAJJBJTSOZGPU-JVSAHFFESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.42
• 重原子数：
  33.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  90.54
• 氢给体数：
  3.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (3R,6R,9S)-3-benzyl-9-((S)-sec-butyl)-6,7-dimethyl-1,4,7,10-tetraazacycloheptadec-15-ene-2,5,8-trione 在 5% Pd/Al₂O₃ 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 生成 (3R,6R,9S)-3-benzyl-9-[(2S)-butan-2-yl]-6,7-dimethyl-1,4,7,10-tetrazacycloheptadecane-2,5,8-trione
  参考文献：
  名称：

  Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic

  摘要：

  High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel ago fists against this G-protein coupled receptor. Early hits such as 1 (K-i = 86 nM, EC50 = 134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (K-i = 16 nM, EC50 = 29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' beta-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

  DOI：

  10.1021/jm2007062
• 作为产物：
  描述：

  5-己烯-1-醇 、 (benzo[d]thiazol-2-ylsulfonyl)-L-isoleucine 、 Carbamic acid, [(2Z)-4-hydroxy-2-butenyl]-, 9H-fluoren-9-ylmethyl ester 、 Fmoc-D-苯丙氨酸 、 N-芴甲氧羰酰基-N-甲基-D-丙氨酸 在 吡啶 、 trityl chloride polystyrene resin 、 二乙基异丙基胺 、 哌啶 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 为溶剂， 生成 (3R,6R,9S)-3-benzyl-9-((S)-sec-butyl)-6,7-dimethyl-1,4,7,10-tetraazacycloheptadec-15-ene-2,5,8-trione
  参考文献：
  名称：

  Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic

  摘要：

  High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel ago fists against this G-protein coupled receptor. Early hits such as 1 (K-i = 86 nM, EC50 = 134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (K-i = 16 nM, EC50 = 29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' beta-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

  DOI：

  10.1021/jm2007062