1-amino-N-(cyanomethyl)cyclohexanecarboxamide methanesulfonate

• 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: 1-amino-N-(cyanomethyl)cyclohexanecarboxamide methanesulfonate
• 英文别名: 1-Amino-n-cyanomethylcyclohexanecarboxamide methanesulfonic acid salt；1-amino-N-(cyanomethyl)cyclohexane-1-carboxamide;methanesulfonic acid
• 化学式: CH₄O₃S*C₉H₁₅N₃O
• 分子量: 277.345
• InChiKey: CRBBAAIFAPYYLT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.21
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  142
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-amino-N-(cyanomethyl)cyclohexanecarboxamide methanesulfonate 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 N-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzamide
  参考文献：
  名称：

  Design and Synthesis of Tri-Ring P₃ Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K

  摘要：

  We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P-2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/ L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.

  DOI：

  10.1021/jm058198r
• 作为产物：
  描述：

  1-(N-叔丁氧羰基氨基)环己烷甲酸 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 1-amino-N-(cyanomethyl)cyclohexanecarboxamide methanesulfonate
  参考文献：
  名称：

  Design and Synthesis of Tri-Ring P₃ Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K

  摘要：

  We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P-2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/ L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.

  DOI：

  10.1021/jm058198r

文献信息

• Novel compounds and compositions as protease inhibitors
  申请人：AXYS PHARMACEUTICALS, INC.

  公开号：US20020086996A1

  公开（公告）日：2002-07-04

  The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

  本发明涉及一种新颖的N-氰甲基酰胺，它们是半胱氨酸蛋白酶抑制剂，以及它们的药用盐和N-氧化物，它们作为治疗剂的用途以及它们的制备方法。
• Compounds and compositions as protease inhibitors
  申请人：Axys Pharmaceuticals, Inc.

  公开号：US06593327B2

  公开（公告）日：2003-07-15

  The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

  本发明涉及一种新型N-氰甲基酰胺，它们是半胱氨酸蛋白酶抑制剂，其药学上可接受的盐和N-氧化物，以及它们作为治疗剂的用途和制备方法。
• Lysosomotropism of Basic Cathepsin K Inhibitors Contributes to Increased Cellular Potencies against Off-Target Cathepsins and Reduced Functional Selectivity
  作者：Jean-Pierre Falgueyret、Sylvie Desmarais、Renata Oballa、W. Cameron Black、Wanda Cromlish、Karine Khougaz、Sonia Lamontagne、Frederic Massé、Denis Riendeau、Sylvie Toulmond、M. David Percival

  DOI：10.1021/jm0504961

  日期：2005.12.1

  The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The arylpiperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are similar to 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-containing analogues do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were observed in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.
• N-CYANOMETHYLAMIDES AS PROTEASE INHIBITORS
  申请人：AXYS PHARMACEUTICALS, INC.

  公开号：EP1161415A2

  公开（公告）日：2001-12-12
• US6476026B1
  申请人：——

  公开号：US6476026B1

  公开（公告）日：2002-11-05