2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde | 1202647-49-1

• 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: 2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde
• 英文别名: 2'-(pyrrolidine-1-sulfonyl)-biphenyl-4-carbaldehyde；2'-(Pyrrolidin-1-ylsulfonyl)-[1,1'-biphenyl]-4-carbaldehyde；4-(2-pyrrolidin-1-ylsulfonylphenyl)benzaldehyde
• CAS: 1202647-49-1
• 化学式: C₁₇H₁₇NO₃S
• 分子量: 315.393
• InChiKey: BTKUAPYQFWWZIT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  62.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 2-甲基-n-((2’-(吡咯烷-1-基磺酰基)联苯-4-基)甲基)丙烷-1-胺盐酸盐
  参考文献：
  名称：

  Design and Discovery of a Selective Small Molecule κ Opioid Antagonist (2-Methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242)

  摘要：

  By use of parallel chemistry coupled with physicochemical property design, a series of selective kappa opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro kappa antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the kappa K-i and the free brain drug levels. This strategy identified 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.

  DOI：

  10.1021/jm2006035
• 作为产物：
  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

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。
• Design and Discovery of a Selective Small Molecule κ Opioid Antagonist (2-Methyl-<i>N</i>-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242)
  作者：Patrick R. Verhoest、Aarti Sawant Basak、Vinod Parikh、Matthew Hayward、Gregory W. Kauffman、Vanessa Paradis、Stanton F. McHardy、Stafford McLean、Sarah Grimwood、Anne W. Schmidt、Michelle Vanase-Frawley、Jodi Freeman、Jeffrey Van Deusen、Loretta Cox、Diane Wong、Spiros Liras

  DOI：10.1021/jm2006035

  日期：2011.8.25

  By use of parallel chemistry coupled with physicochemical property design, a series of selective kappa opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro kappa antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the kappa K-i and the free brain drug levels. This strategy identified 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.
• Metabolism and clinical pharmacokinetics of 2-methyl-<i>n-</i>(2′-(pyrrolidinyl-1-ylsulfonyl)-<i>n</i>-[1,1′-biphenyl]-4-yl)propran-1-amine: insights into monoamine oxidase- and CYP-mediated disposition by integration of<i>in vitro</i>ADME tools
  作者：Aarti Sawant Basak、Wonkyung Byon、Elaine Tseng-Lovering、Carrie Funk、Linda Wood、Chang Lin、Marielle Delnomdedieu、Patrick Verhoest、Vinod Parikh、Loretta M. Cox、Emily Miller、Hongying Gao、Ronald S. Obach

  DOI：10.3109/00498254.2013.850552

  日期：2014.5

  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.