S-(2-amino-5-carbethoxyphenyl)-4,6-dimethyl-2-thiopyrimidine

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: S-(2-amino-5-carbethoxyphenyl)-4,6-dimethyl-2-thiopyrimidine
• 英文别名: Ethyl 4-amino-3-(4,6-dimethylpyrimidin-2-yl)sulfanylbenzoate
• 化学式: C₁₅H₁₇N₃O₂S
• 分子量: 303.385
• InChiKey: CODWCLSFBUBZAI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  S-(2-amino-5-carbethoxyphenyl)-4,6-dimethyl-2-thiopyrimidine 在 盐酸 、 sodium tetrahydroborate 、 乙醇 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 76.0h， 生成 N-<2-(methylthio)-4-carbethoxyphenyl>-4,6-dimethyl-2-pyrimidinamine
  参考文献：
  名称：

  Non-Peptide Corticotropin-Releasing Hormone Antagonists:  Syntheses and Structure−Activity Relationships of 2-Anilinopyrimidines and -triazines

  摘要：

  Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [I-125]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (K-i = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than a-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH(1) receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH(1) receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1) K-i = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.

  DOI：

  10.1021/jm980222w
• 作为产物：
  描述：

  4-氨基-3-碘苯甲酸乙酯 、 4,6-二甲基-2-巯基嘧啶 在 铜 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以95%的产率得到S-(2-amino-5-carbethoxyphenyl)-4,6-dimethyl-2-thiopyrimidine
  参考文献：
  名称：

  Non-Peptide Corticotropin-Releasing Hormone Antagonists:  Syntheses and Structure−Activity Relationships of 2-Anilinopyrimidines and -triazines

  摘要：

  Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [I-125]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (K-i = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than a-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH(1) receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH(1) receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1) K-i = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.

  DOI：

  10.1021/jm980222w

文献信息

• Non-Peptide Corticotropin-Releasing Hormone Antagonists:  Syntheses and Structure−Activity Relationships of 2-Anilinopyrimidines and -triazines
  作者：Argyrios G. Arvanitis、Paul J. Gilligan、Robert J. Chorvat、Robert S. Cheeseman、Thomas E. Christos、Rajagopal Bakthavatchalam、James P. Beck、Anthony J. Cocuzza、Frank W. Hobbs、Richard G. Wilde、Charles Arnold、Dennis Chidester、Matthew Curry、Liqi He、Andrea Hollis、John Klaczkiewicz、Paul J. Krenitsky、Joseph P. Rescinito、Everett Scholfield、Steven Culp、Errol B. De Souza、Lawrence Fitzgerald、Dimitri Grigoriadis、S. William Tam、Y. Nancy Wong、Shiew-Mei Huang、Helen L. Shen

  DOI：10.1021/jm980222w

  日期：1999.3.1

  Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [I-125]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (K-i = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than a-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH(1) receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH(1) receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1) K-i = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.