PF-04455242 | 1202647-54-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: PF-04455242
• 英文别名: PF-4455242；PF-4455242 free base；2-methyl-N-[[4-(2-pyrrolidin-1-ylsulfonylphenyl)phenyl]methyl]propan-1-amine
• CAS: 1202647-54-8
• 化学式: C₂₁H₂₈N₂O₂S
• 分子量: 372.532
• InChiKey: OWVIKBRKPCTDEP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  57.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  PF-04455242 在 recombinant human monoamine oxidase A 、 magnesium chloride 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.17h， 生成 2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde
  参考文献：
  名称：

  Metabolism and clinical pharmacokinetics of 2-methyl-n-(2′-(pyrrolidinyl-1-ylsulfonyl)-n-[1,1′-biphenyl]-4-yl)propran-1-amine: insights into monoamine oxidase- and CYP-mediated disposition by integration ofin vitroADME tools

  摘要：

  1. In early discovery stages, 2-methyl-N-(2'-(pyrrolidinyl-1-ylsulfonyl)-[ 1,1'-biphenyl]-4-yl) propan- 1-amine (PBPA) demonstrated monoamine oxidase A (MAO-A) and cytochrome P450 (CYP)-mediated clearance. While human liver microsomes predicted low CLb PBPA demonstrated a moderate CLp/F in humans. The plasma pharmacokinetic (PK) of PBPA was characterized by unexpected high inter-individual variability. Hence, a retrospective analysis was undertaken to understand the disposition processes of PBPA, by applying in vitro mechanistic tools.2. The in vitro-to-in vivo of rat CLb of PBPA was calculated as similar to that of human, suggesting rat to be a better predictor of a MAO-A/CYP substrate, but not dog or monkey; this is consistent with differences in expression of MAO-A in rat, dog, monkey and human. Fraction metabolized (f(m)) of human MAO A (hMAO-A) (50%), CYP3A4 (8%), CYP3A5 (16%) and CYP2D6 (29%) was determined, in vitro.3. While the f(m) of CYP3A5 was >50%, Michaelis-Menten kinetics demonstrated that it was a higher capacity pathway compared with MAO-A, 2D6 and 3A4. This was consistent with strong association of dose-normalized plasma C-max and area under the plasma concentration time curve (AUC(0-tlast)) of PBPA with CYP3A5 genotype, but not with genotype of CYP2D6.4. This investigation demonstrates the value of integrating in vitro mechanistic tools to gain comprehensive understanding of disposition properties of drug candidates, in a discovery paradigm and prior to the investment in clinical trials.

  DOI：

  10.3109/00498254.2013.850552
• 作为产物：
  描述：

  2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde 、 异丁胺 在 异丁胺 作用下， 以82.1的产率得到PF-04455242
  参考文献：
  名称：

  Diaryl Compounds and Uses Thereof

  摘要：

  该发明涉及公式I化合物的衍生物，其中R1至R7和X1至X6的定义如本文所述。该发明涉及其用于治疗由kappa阿片受体（KORs）介导的疾病、状况和/或障碍的用途。具体而言，该化合物是KORs的选择性拮抗剂，并且相对于μ和δ阿片受体高度选择性。

  公开号：

  US20100035873A1

文献信息

• Diaryl Compounds and Uses Thereof
  申请人：Verhoest Patrick

  公开号：US20100035873A1

  公开（公告）日：2010-02-11

  The invention relates to derivatives of a compound of formula I: wherein R 1 to R 7 and X 1 to X 6 are as defined herein. The invention relates to the uses thereof for treating diseases, conditions and/or disorders mediated by kappa opioid receptors (KORs). Specifically, the compounds are selective antagonists of KORs and are highly selective to KORs relative to mu and delta opioid receptors.

  本发明涉及公式I的化合物的衍生物：其中R1至R7和X1至X6的定义如本文所述。本发明涉及其用于治疗由kappa阿片受体（KORs）介导的疾病、状况和/或障碍的用途。具体而言，这些化合物是KORs的选择性拮抗剂，并且相对于mu和delta阿片受体高度选择性地作用于KORs。
• 1-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS
  申请人：RESEARCH TRIANGLE INSTITUTE

  公开号：US20150005315A1

  公开（公告）日：2015-01-01

  Provided are compounds represented by the formula: where R, Y 3 , R 1 , R 2 , R 3 , R 4 , R 6 , G, R 7 , E 1 , E 2 , A, B, W, X, Y and Z are as defined herein.

  提供的化合物由以下公式表示：其中R，Y3，R1，R2，R3，R4，R6，G，R7，E1，E2，A，B，W，X，Y和Z的定义如下。
• Substituted 1,2,3,4-tetrahydroisoquinolines as kappa opioid antagonists
  申请人：Research Triangle Institute

  公开号：US11292783B2

  公开（公告）日：2022-04-05

  Potent opioid receptor antagonists of formula (I) and their use as pharmacotherapies for treating depression, anxiety, schizophrenia, eating disorders, and addiction to cocaine, methamphetamine, nicotine, alcohol, and opiates are disclosed. More specifically, the disclosure provides potent and selective kappa opioid receptor antagonist compounds, pharmaceutical compositions of those compounds and uses of those compounds to ameliorate or treat addictions, eating disorders, etc.

  本发明公开了式(I)的强效阿片受体拮抗剂及其作为治疗抑郁症、焦虑症、精神分裂症、饮食失调以及可卡因、甲基苯丙胺、尼古丁、酒精和阿片剂成瘾的药物疗法的用途。 更具体地说，本公开提供了强效和选择性卡巴阿片受体拮抗剂化合物、这些化合物的药物组合物以及这些化合物在改善或治疗成瘾、饮食失调等方面的用途。
• TETRAHYDROISOQUINOLINE KAPPA OPIOID ANTAGONISTS
  申请人：Research Triangle Institute

  公开号：EP3512832B1

  公开（公告）日：2021-05-19
• METHODS FOR TREATING FIBROSIS
  申请人：CHILDREN'S HOSPITAL MEDICAL CENTER

  公开号：US20190247373A1

  公开（公告）日：2019-08-15

  Some embodiments of the invention include methods for treating an animal for fibrosis comprising one or more administrations of one or more compositions comprising one or more opioid receptor inhibitors. Other embodiments of the invention further include other fibrosis treatments. Still other embodiments of the invention include methods for treating a human for idiopathic pulmonary fibrosis, comprising administering one or more compositions comprising naltrexone and optionally administering one or more compositions comprising pirfenidone, nintedanib, or both. Additional embodiments of the invention are also discussed herein.