| 918958-59-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• CAS: 918958-59-5
• 化学式: C₁₆H₂₅NO₃
• 分子量: 279.379
• InChiKey: NTFKBIIULACDPR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.68
• 重原子数：
  20.0
• 可旋转键数：
  6.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  58.56
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  、 、 Boc-D-缬氨酸 、 N-tert-butoxycarbonyl-L-norvaline 生成 (6S,9R,12R)-12-[(4-hydroxyphenyl)methyl]-9-propan-2-yl-6-propyl-4,7,10,13-tetrazabicyclo[15.4.0]henicosa-1(21),17,19-triene-5,8,11-trione
  参考文献：
  名称：

  Discovery of a New Class of Macrocyclic Antagonists to the Human Motilin Receptor

  摘要：

  A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.

  DOI：

  10.1021/jm0606600
• 作为产物：
  描述：

  2-甲基-2-丙基[2-(2-溴苯基)乙基]氨基甲酸酯 在 platinum(IV) oxide 、 双(乙腈)氯化钯(II) 、 copper(l) iodide 、 三叔丁基膦 、 氢气 、 二异丙胺 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 生成
  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