1-[1-(4-methanesulfonylphenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea | 1287760-87-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-[1-(4-methanesulfonylphenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea
• 英文别名: 1-[1-(4-Methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea；1-[[1-(4-methylsulfonylphenyl)-5-phenylpyrazol-3-yl]methyl]-3-[4-(trifluoromethoxy)phenyl]urea
• CAS: 1287760-87-5
• 化学式: C₂₅H₂₁F₃N₄O₄S
• 分子量: 530.527
• InChiKey: IAJSBABEUHDARJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-(甲基磺酰基)苯肼盐酸盐 在 lithium aluminium tetrahydride 、 sodium azide 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 1-[1-(4-methanesulfonylphenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationship Studies of Urea-Containing Pyrazoles as Dual Inhibitors of Cyclooxygenase-2 and Soluble Epoxide Hydrolase

  摘要：

  A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual:inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 211, and 21j) in which both the 1,5-diaryl-pyrazole group aid the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of:both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.

  DOI：

  10.1021/jm2001376

文献信息

• PYRAZOLE INHIBITORS OF COX-2 AND SEH
  申请人：Hammock Bruce D.

  公开号：US20140038923A1

  公开（公告）日：2014-02-06

  The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e., a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e., a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro, ex vivo and in vivo. The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo.

  本发明提供了化合物和组合物，例如一系列化合物，其中1,5-联苯吡唑基通过不可断裂的共价链与尿素基结合，这些化合物可用作双COX-2/sEH抑制剂。本文披露的化合物具有与花生四烯酸级联相关的活性。这些化合物的活性是使用大鼠脂多糖（LPS）诱导的疼痛模型进行证明的。与同等剂量的Celecoxib（即COX-2抑制剂）以及同等剂量的t-AUCB（即sEH抑制剂）相比，本发明的化合物表现出优越的抗痛觉过敏活性，也与同时给予的Celecoxib和t-AUCB的同等剂量相比。本发明的双重抑制剂在伤害性行为测定中显示出增强的体内抗痛觉过敏活性。此外，本发明的化合物还表现出对内皮细胞（HUVEC）具有强效的抗血管生成作用，并且在体外、体内和体内抑制血管生成。本发明的双重抑制剂还表现出抗血管生成效应，可以减缓体内乳腺肿瘤生长。
• METHODS OF IMPROVING CANCER CHEMOTHERAPY
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20200197368A1

  公开（公告）日：2020-06-25

  Provided are methods and compositions for prolonging survival and/or reducing or inhibiting tumor growth in a cancer subject receiving a regimen of one or more chemotherapeutic agents, an inhibitor of soluble epoxide hydrolase (sEHi) and a non-steroidal anti-inflammatory drug (NSAID) that inhibits one or more enzymes selected from the group consisting of cyclo-oxygenase (“COX”)-1, COX-2, and 5-lipoxygenase (“5-LOX”). The methods and compositions decrease toxicity and/or adverse side effects in subjects receiving a regimen of one or more chemotherapeutic agents.
• METHODS OF IMPROVING CELL-BASED THERAPY
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20210145891A1

  公开（公告）日：2021-05-20

  Provided are methods for improving the efficacy and success of cell-based therapies by administration of stem cells which have been preconditioned with an inhibitor of soluble epoxide hydrolase (sEHI), as well as kits, stents and patches for administering sEHI-preconditioned stem cells, as sole active agent or in combination with an agent that increases the production and or levels of EETs.
• METHODS OF INHIBITING FORMATION OF ALPHA SYNUCLEIN AGGREGATES
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20210161881A1

  公开（公告）日：2021-06-03

  Provided are methods of preventing, delaying, mitigating, reducing and/or inhibiting alpha-synuclein aggregates in the brains of a subject at risk of developing or suffering a cognitive disease associated with, caused and/or mediated at least in part by alpha-synuclein aggregates, for example, Parkinson's Disease or Dementia with Lewy Bodies (DLB).
• DUAL INHIBITORS OF SOLUBLE EPOXIDE HYDROLASE AND METHODS OF USE THEREOF
  申请人：OROX Biosciences, Inc.

  公开号：US20220218667A1

  公开（公告）日：2022-07-14

  Disclosed herein are methods to treatment of inflammatory and fibrotic progression, for example, idiopathic pulmonary fibrosis (IPF) with a dual inhibitor of soluble epoxide hydrolase inhibitors (sEH) and a secondary target. In particular, the invention relates to treatment of fibrotic progression with a dual inhibitor of sEH and COX-2. In one embodiment, IPF is treated with 4-(5-phenyl-3-3-[3-(4-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide (PTUPB) or a derivative thereof. Also disclosed herein are compositions useful in treatment of fibrotic progression.