(3R,6S,9R,12R)-12-benzyl-6-[(2S)-butan-2-yl]-9-ethyl-3-methyl-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione | 1351469-14-1

• 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,6S,9R,12R)-12-benzyl-6-[(2S)-butan-2-yl]-9-ethyl-3-methyl-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione
• CAS: 1351469-14-1
• 化学式: C₃₁H₄₄N₄O₄
• 分子量: 536.715
• InChiKey: QTYKFOHHZIMYIT-SBPKXREESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  109
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (benzo[d]thiazol-2-ylsulfonyl)-L-isoleucine 、 、 、 Carbamic acid, [3-[2-[(1R)-2-hydroxy-1-methylethoxy]phenyl]propyl]-,1-(3,5-dimethoxyphenyl)-1-methylethyl ester 在 三乙基硅烷 、 二乙基异丙基胺 、 C₂₃H₂₂NOPolS 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三氟乙酸 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 为溶剂， 生成 (3R,6S,9R,12R)-12-benzyl-6-[(2S)-butan-2-yl]-9-ethyl-3-methyl-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-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

文献信息

• Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic
  作者：Hamid R. Hoveyda、Eric Marsault、René Gagnon、Axel P. Mathieu、Martin Vézina、Annick Landry、Zhigang Wang、Kamel Benakli、Sylvie Beaubien、Carl Saint-Louis、Martin Brassard、Jean-François Pinault、Luc Ouellet、Shridhar Bhat、Mahesh Ramaseshan、Xiaowen Peng、Laurence Foucher、Sophie Beauchemin、Patrick Bhérer、Daniel F. Veber、Mark L. Peterson、Graeme L. Fraser

  DOI：10.1021/jm2007062

  日期：2011.12.22

  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.