N-[2-[2-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]tetrazol-5-yl]-5-hydroxy-4-methoxyphenyl]-4-oxochromene-2-carboxamide | 894406-60-1

• 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: N-[2-[2-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]tetrazol-5-yl]-5-hydroxy-4-methoxyphenyl]-4-oxochromene-2-carboxamide
• CAS: 894406-60-1
• 化学式: C₃₇H₃₄N₆O₇
• 分子量: 674.713
• InChiKey: VGTDCDPQLPRSJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  50
• 可旋转键数：
  10
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  150
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  N-[2-[2-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]tetrazol-5-yl]-5-hydroxy-4-methoxyphenyl]-4-oxochromene-2-carboxamide 、 [11C]methyl triflate 在 四丁基氢氧化铵 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 0.07h， 生成 [¹¹C]HM30181
  参考文献：
  名称：

  Interaction of HM30181 with P-glycoprotein at the murine blood–brain barrier assessed with positron emission tomography

  摘要：

  HM30181, a potent and selective inhibitor of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp), was shown to enhance oral bioavailability and improve antitumour efficacy of paclitaxel in mouse tumour models. In search for a positron emission tomography (PET) radiotracer to visualise Pgp expression levels at the blood-brain barrier (BBB), we examined the ability of HM30181 to inhibit Pgp at the murine BBB. HM30181 was shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC50, tariquidar: 8.2 +/- 2.0 nM, HM30181: 13.1 +/- 2.3 nM). PET scans with the Pgp substrate (R)-[C-11]verapamil in FVB wild-type mice pretreated i.v. with HM30181 (10 or 21 mg/kg) failed to show significant increases in (R)-[C-11]verapamil brain uptake compared with vehicle treated animals. PET scans with [C-11]HM30181 showed low and not significantly different brain uptake of [C-11]HM30181 in wild-type, Mdr1a/b((-/-)) and Bcrp1((-/-)) mice and significantly, i.e. 4.7-fold (P < 0.01), higher brain uptake, relative to wild-type animals, in Mdr1a/b((-/-)) Bcrp1((-/-)) mice. This was consistent with HM30181 being at microdoses a dual substrate of Pgp and breast cancer resistance protein (Bcrp). In vitro autoradiography on low (EMT6) and high (EMT6Ar1.0) Pgp expressing murine breast tumour sections showed 1.9 times higher binding of [C-11]HM30181 in EMT6Ar1.0 tumours (P < 0.001) which was displaceable with unlabelled tariquidar, elacridar or HM30181 (1 mu M). Our data suggest that HM30181 is not able to inhibit Pgp at the murine BBB at clinically feasible doses and that [C-11]HM30181 is not suitable as a PET tracer to visualise cerebral Pgp expression levels. (C) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejphar.2012.09.013
• 作为产物：
  描述：

  (E)-N'-(4-(benzyloxy)-5-methoxy-2-nitrobenzylidene)-4-methylbenzenesulfonohydrazide 在 盐酸 、 茴香硫醚 、 1-羟基苯并三唑 、 一水合肼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 sodium nitrite 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.25h， 生成 N-[2-[2-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]tetrazol-5-yl]-5-hydroxy-4-methoxyphenyl]-4-oxochromene-2-carboxamide
  参考文献：
  名称：

  Interaction of HM30181 with P-glycoprotein at the murine blood–brain barrier assessed with positron emission tomography

  摘要：

  HM30181, a potent and selective inhibitor of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp), was shown to enhance oral bioavailability and improve antitumour efficacy of paclitaxel in mouse tumour models. In search for a positron emission tomography (PET) radiotracer to visualise Pgp expression levels at the blood-brain barrier (BBB), we examined the ability of HM30181 to inhibit Pgp at the murine BBB. HM30181 was shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC50, tariquidar: 8.2 +/- 2.0 nM, HM30181: 13.1 +/- 2.3 nM). PET scans with the Pgp substrate (R)-[C-11]verapamil in FVB wild-type mice pretreated i.v. with HM30181 (10 or 21 mg/kg) failed to show significant increases in (R)-[C-11]verapamil brain uptake compared with vehicle treated animals. PET scans with [C-11]HM30181 showed low and not significantly different brain uptake of [C-11]HM30181 in wild-type, Mdr1a/b((-/-)) and Bcrp1((-/-)) mice and significantly, i.e. 4.7-fold (P < 0.01), higher brain uptake, relative to wild-type animals, in Mdr1a/b((-/-)) Bcrp1((-/-)) mice. This was consistent with HM30181 being at microdoses a dual substrate of Pgp and breast cancer resistance protein (Bcrp). In vitro autoradiography on low (EMT6) and high (EMT6Ar1.0) Pgp expressing murine breast tumour sections showed 1.9 times higher binding of [C-11]HM30181 in EMT6Ar1.0 tumours (P < 0.001) which was displaceable with unlabelled tariquidar, elacridar or HM30181 (1 mu M). Our data suggest that HM30181 is not able to inhibit Pgp at the murine BBB at clinically feasible doses and that [C-11]HM30181 is not suitable as a PET tracer to visualise cerebral Pgp expression levels. (C) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejphar.2012.09.013