3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-[3-(7-hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-[3-(7-hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid
• 英文别名: (S)-3-{3-[3-(7-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-2-oxo-imidazolidin-1-yl}-3-(6-methoxy-pyridin-3-yl)-propionic acid；(3S)-3-[3-[3-(7-hydroxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-2-oxoimidazolidin-1-yl]-3-(6-methoxypyridin-3-yl)propanoic acid
• 化学式: C₂₃H₂₉N₅O₅
• 分子量: 455.514
• InChiKey: YSUOCWJZGZEUQT-OYKVQYDMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  128
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-甲氧基吡啶 在 palladium dihydroxide 盐酸 、 4-二甲氨基吡啶 、 氢氧化钾 、 sodium hydroxide 、 potassium permanganate 、 正丁基锂 、 氢气 、 溴 、 sodium acetate 、 sodium cyanoborohydride 、 溶剂黄146 、 N,N-二异丙基乙胺 、 potassium bromide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 乙酸乙酯 、 1,2-二氯乙烷 、 异丙醇 为溶剂， 反应 97.25h， 生成 3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-[3-(7-hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid
  参考文献：
  名称：

  Nonpeptide α_vβ₃ Antagonists. 8. In Vitro and in Vivo Evaluation of a Potent α_vβ₃ Antagonist for the Prevention and Treatment of Osteoporosis

  摘要：

  3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]-imidazolidin-1-yl}propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC50 = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.

  DOI：

  10.1021/jm030306r

文献信息

• Alpha v integrin receptor antagonists
  申请人：——

  公开号：US20020049224A1

  公开（公告）日：2002-04-25

  The present invention relates to novel compounds formed by metabolic conversion of compounds of structural formula (1), pharmaceutical compositions containing such compounds, and their use as &agr;v&bgr;3 integrin receptor antagonists. The compounds of the present invention are useful for inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, and metastatic tumor growth. They are particularly useful for inhibiting bone resorption and for the treatment and prevention of osteoporosis. 1

  本发明涉及通过化合物的代谢转化形成的新化合物，包含这种化合物的药物组合物，以及它们作为αvβ3整合素受体拮抗剂的用途。本发明的化合物对于抑制骨吸收、再狭窄、血管生成、糖尿病视网膜病变、黄斑变性、炎症性关节炎、癌症和转移性肿瘤生长具有用途。它们特别适用于抑制骨吸收以及治疗和预防骨质疏松症。
• US6426353B1
  申请人：——

  公开号：US6426353B1

  公开（公告）日：2002-07-30
• Nonpeptide α_vβ₃ Antagonists. 8. In Vitro and in Vivo Evaluation of a Potent α_vβ₃ Antagonist for the Prevention and Treatment of Osteoporosis
  作者：John H. Hutchinson、Wasyl Halczenko、Karen M. Brashear、Michael J. Breslin、Paul J. Coleman、Le T. Duong、Carmen Fernandez-Metzler、Michael A. Gentile、John E. Fisher、George D. Hartman、Joel R. Huff、Donald B. Kimmel、Chih-Tai Leu、Robert S. Meissner、Kara Merkle、Rose Nagy、Brenda Pennypacker、James J. Perkins、Thomayant Prueksaritanont、Gideon A. Rodan、Sandor L. Varga、Greg A. Wesolowski、Amy E. Zartman、Sevgi B. Rodan、Mark E. Duggan

  DOI：10.1021/jm030306r

  日期：2003.10.1

  3(S)-(6-Methoxypyridin-3-yl)-3-2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]-imidazolidin-1-yl}propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC50 = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.