JP2014185133A - Inhibitor of abc transporter - Google Patents

Inhibitor of abc transporter Download PDF

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JP2014185133A
JP2014185133A JP2013080745A JP2013080745A JP2014185133A JP 2014185133 A JP2014185133 A JP 2014185133A JP 2013080745 A JP2013080745 A JP 2013080745A JP 2013080745 A JP2013080745 A JP 2013080745A JP 2014185133 A JP2014185133 A JP 2014185133A
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abc transporter
nitroimidazole
dihydroxy
brain
hydroxymethylpropyloxymethyl
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JP6170327B2 (en
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Nobuo Kubota
信雄 久保田
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Pola Pharma Inc
株式会社ポーラファルマ
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Abstract

PROBLEM TO BE SOLVED: To provide means for enhancing drug delivery to the brain tumor portion but not to the normal tissues of the brain.SOLUTION: Provided is an inhibitor of ABC transporter under the conditions of low oxygen, which comprises 1-(2,3-dihydroxy-1-hydroxymethyl propyloxymethyl)-2-nitroimidazole of the following formula. ABC-transporters to be inhibited are preferably those related to cancer cells or brain-blood barriers.

Description

  The present invention relates to an ABC transporter inhibitor that inhibits an ABC transporter involved in drug excretion in a hypoxic state. More specifically, the present invention relates to a cancer in which the effect of an anticancer drug or the like is reduced due to excessive drug excretion. ABC transporter inhibitors useful for the treatment of

  In cancer chemotherapy, the development of resistance to anticancer drugs has become an important issue that affects the therapeutic effect. The development of resistance to drugs is thought to be due to drug excretion by ABC transporters such as MDR. As means for inhibiting such drug excretion, quinoline derivatives have been developed and used for clinical trials, but development has been suspended (see Non-Patent Documents 1 and 2). In addition to these, transporter inhibitors include calcium antagonist verapamil, central drug desipramine, etc., all of which have higher main drug effects than inhibitory effects, and transporter inhibitors are Application was difficult.

  On the other hand, in cancer chemotherapy, there is a problem of hypoxic cells as well as the development of resistance by the transporter. Hypoxic cells have a high resistance to radiation, which is a major obstacle to cancer radiotherapy. As a means to solve this, a radiosensitizer using a 2-nitroimidazole derivative has been developed and is currently in clinical trials. (For example, refer to Patent Documents 1, 2, and 3). The hypoxic ABC transporter inhibitor of the present invention, 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole, is also radiosensitized to hypoxic cells. Has an effect. This is a compound that reduces the side effects due to the central orientation of misonidazole and exerts a hypoxic cell radiosensitization effect. In general, 2-nitroimidazole has a high orientation of the nervous system, and is therefore likely to develop neurotoxicity. It is known that misonidazole or RK-28 (1- (4-hydroxybutan-2-en-1-yl) -2-nitroimidazole) is also oriented in the brain across the brain-vascular barrier. This is said to be one of the causes of neurotoxicity. In addition, 2-nitroimidazole derivatives are easily oriented to hypoxic cells regardless of whether they are cancer cells or normal cells, and studies as markers for hypoxic cells are also being promoted (for example, Non-Patent Documents 3 and 4). , See Patent Document 4). Although having such a background, it was not known at all that such a compound inhibits the transporter in a hypoxic state regardless of the presence or absence of irradiation.

  The cerebral blood flow barrier is an organ that prevents harmful substances from flowing into the brain, and the reality is that chemical substances are discharged from the brain into the blood vessels by ABC transporters arranged on the blood vessels. It is known that there is. Because of the presence of these organs, the brain is not exposed to harmful substances. On the other hand, when treating brain diseases such as brain tumors, the cerebral blood flow barrier It interferes with arrival and makes treatment difficult. In other words, it can be said that development of a means for inhibiting the cerebral blood flow barrier when desired is desired. Furthermore, the development of such means is considered to be applicable to the treatment of cancer resistant to the above-mentioned anticancer agents, and it was also desired in this sense. Particularly, hypoxic cells having radiation resistance are strongly desired because the therapeutic effect can be remarkably improved if a drug can reach here. Furthermore, in brain tumors and the like, it is an important issue to prevent the drug from reaching parts other than the tumor.

Sato W, et. al. Cancer Res. 1991; 51 (9): 2420-4 Katayama R, et. al. Cancer Sci. 2009; 100 (11): 2060-8 Moenich D. et. al. Phys Med Biol. 2012; 57 (6): 1675-1684 Shibahara I. et. al. J Neurosurg. 2010; 113 (2): 358-68.

JP 2003-321459 A JP 2007-326814 A WO2008 / 090732 pamphlet WO01 / 019779 pamphlet

  The present invention has been made under such circumstances, and it is an object of the present invention to provide a means for improving the drug reachability only to the brain tumor part in a brain tumor and not improving the drug reach to the normal part of the brain. And

  In view of such a situation, the present inventors have made intensive research efforts to improve the drug reachability only to the brain tumor part and not to improve the drug arrival to the normal part of the brain in brain tumors. As a result of overlapping, 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole, which has the following structural formula, specifically inhibits the ABC transporter under hypoxic conditions. The present invention has been completed. That is, the present invention is as follows.

1- (2,3-Dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole

<1> An ABC transporter inhibitor under low oxygen conditions, comprising 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole, having the structural formula shown above.
<2> The ABC transporter inhibitor under hypoxic conditions according to <1>, wherein the ABC transporter to be inhibited relates to a cancer cell or blood brain barrier.
<3> The ABC transporter inhibitor under hypoxic conditions according to <1> or <2>, which is used together with an anticancer agent.
<4> The ABC transporter inhibitor under hypoxic conditions according to any one of <1> to <3>, which is used for treatment of an anticancer drug-resistant cancer or brain tumor.

  ADVANTAGE OF THE INVENTION According to this invention, in a brain tumor, the chemical | medical agent reachability only to a brain tumor part can be improved, and the means which does not improve the arrival of a chemical | medical agent to the normal part of a brain can be provided.

  The ABC transporter inhibitor under hypoxic conditions of the present invention is characterized by comprising 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole having the above structure. . Such compounds have four isomers, any of which can be used. That is, 2 (R), 3 (R) -1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (hereinafter sometimes referred to as RR form), 2 (S) , 3 (S) -1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (hereinafter sometimes referred to as SS form), 2 (R), 3 (S)- 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (hereinafter sometimes referred to as RS form) and 2 (S), 3 (R) -1- (2,3 -Dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (hereinafter sometimes referred to as SR form). Moreover, the use with the racemic body which is these mixtures is also possible. Moreover, about the manufacturing method of these compounds, the details are described in Unexamined-Japanese-Patent No. 2003-321459, and it can manufacture according to this. That is, for example, the two hydroxyl groups of erythritol are protected with isopropylidene, the primary hydroxyl group is protected with a benzyl group, dimethoxymethane is reacted with phosphorus pentoxide as a catalyst, and the remaining hydroxyl group is converted to methoxymethyl ether. It is obtained by converting a group into an acetyl group with acetic anhydride and phosphorus pentoxide, condensing this with trimethylsilyl 2-nitroimidazole using a Lewis acid as a catalyst and then deprotecting.

2 (R), 3 (R) -1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole

2 (S), 3 (S) -1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole

2 (R), 3 (S) -1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole

2 (S), 3 (R) -1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole

  In the present invention, when 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole is used as an ABC transporter inhibitor under hypoxic conditions, the preferred dosage is , 10 mg / Kg to 5000 mg / Kg is preferable although it varies depending on the drug used for the subsequent treatment. This is because the administration of such dose of 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole inhibits the ABC transporter at the hypoxic site, thereby Control emissions. Since such a compound does not exhibit such an effect under oxygen conditions, neither the compound itself nor a drug such as an anticancer drug administered thereafter is inhibited from being discharged from the brain or the like in a normal brain. Therefore, it has an advantage of not expressing neurotoxicity. In addition, since only the transporter in the hypoxic state is inhibited, the subsequent drug arrives preferentially over the hypoxic cells with unfavorable treatment results. Can enhance the effect of drugs.

  When administering the ABC transporter inhibitor under the hypoxic condition of the present invention, the route of administration is selected from oral administration, intravenous administration, etc., injection or drip administration, rectal administration with suppositories, etc. In particular, in the case of administration to the brain or the like, administration by injection or infusion that acts accurately on the cerebral blood vessel barrier is preferable.

  The major disease using the ABC transporter inhibitor under hypoxic conditions of the present invention is a disease having a hypoxic region in the lesion, and it is necessary to deliver the drug to the hypoxic region in the lesion It is a certain disease. In such diseases, it is immediately preferable that the ABC transporter interferes with the drug orientation. Suitable examples of such diseases include brain tumors, ischemic heart diseases, cancers that are resistant to radiation and chemotherapeutic agents, such as lung adenocarcinoma, and the like.

  When the ABC transporter inhibitor under hypoxic conditions of the present invention is used, a drug for treating the disease after administration of this agent, an anticancer agent for cancer, and a myocardium for ischemic heart disease It is preferable to administer a protective agent or the like. Such a drug is oriented without being hindered by drug excretion at a site where drug excretion is inhibited by administration of the ABC transporter inhibitor under hypoxic conditions of the present invention. Thus, the effect of the drug can be enhanced.

  Hereinafter, the present invention will be described in more detail with reference to examples.

A cancer-bearing state was created by injecting 1 million C6 cells dispersed in 5 μL of FBS into the brains of 9-week-old WKAH / Hkm rats. While monitoring by MRI, it was confirmed that the size of the brain tumor was 50 mm 3 or more and used for the experiment. Rats, 1- (2,3-dihydroxy-1-hydroxymethyl-propoxymethyl)-2-14 C label in the nitroimidazole RS · SR racemic administered from 4.9MBq tail vein 90 minutes after administration The brain was removed and subjected to microautoradiography. At the same time, hematoxylin / eosin stained (HE stained) specimens were also prepared. Comparing autoradiography and HE-stained specimens, the presence of 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole is deep in brain tumors, and even deep inside brain tumors It turns out that it is dark. Since this deeply stained site does not overlap with the place showing the cell viability of HE staining, it is presumed that hypoxic cells are highly likely to exist. In other words, 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole appears to be oriented in the brain tumor from a site with high hypoxia. In the normal region, the presence of 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole is thin, and the characteristic of being difficult to orient in the original central nervous system has been reconfirmed. . Thus, 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole inhibits the ABC transporter constituting the cerebral blood flow barrier in hypoxia, and drug excretion Therefore, it was estimated that the concentration of 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole in the hypoxic region of the brain tumor was increased.

  1- (2,3-Dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (SR / RS racemate) is said to have high expression of MDR in oxygen and hypoxia conditions in the presence of 10 mM MTT assay was performed using PH69AR (MDR) SCLC cells and MES-SA / Dx5 (MDR). As a comparative example, the same study was performed for MES-SA (WT) cells with low MDR expression. The results are shown in Table 1. As a result, the effects of administration of 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (SR / RS racemate) are almost not affected in cells with low generation of ABC transporters such as MDR. Although there is no, it can be seen that the survival rate under hypoxic conditions is reduced in cells with a high expression level of ABC transporters such as MDR. This is probably because ABC transporter is inhibited in the hypoxic region by 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (SR / RS racemate).

  Using RERF-LC-AI (human lum squamous carcinoma) under hypoxic conditions, anticancer agent and 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (SR / RS racemic) Body) was examined. The method used the MTT assay. The results are shown in Table 2. As a result, the presence of 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (SR / RS racemate) inhibits the efflux transporter under hypoxic conditions. Was estimated.

Industrial application fields

  The present invention can be applied to medicine.

Claims (4)

  1. An ABC transporter inhibitor under hypoxic conditions, comprising 1- (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole, having the following structural formula.
    1- (2,3-Dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole
  2.   The ABC transporter inhibitor under hypoxic conditions according to claim 1, wherein the ABC transporter to be inhibited is related to cancer cells or the blood brain barrier.
  3.   The ABC transporter inhibitor under hypoxic conditions according to claim 1 or 2, wherein the ABC transporter inhibitor is used together with an anticancer agent.
  4.   The ABC transporter inhibitor under hypoxic conditions according to any one of claims 1 to 3, which is used for treatment of an anticancer drug-resistant cancer or a brain tumor.
JP2013080745A 2013-03-22 2013-03-22 ABC transporter inhibitor Active JP6170327B2 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5929104A (en) * 1997-04-02 1999-07-27 Pola Chemical Industries, Inc. Method for inducing apoptosis of cancer cell
JP2007230958A (en) * 2006-03-03 2007-09-13 Pola Chem Ind Inc Enhancer of radiosensitization ability in hypoxic cell radiosensitizer
JP2007302609A (en) * 2006-05-12 2007-11-22 Pola Chem Ind Inc Agent for reinforcing radiation-sensitizing ability in hypoxic cell radiation sensitizer
CN101642452A (en) * 2008-08-06 2010-02-10 株式会社宝丽制药 Radiation sensitizer used for brain tumor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5929104A (en) * 1997-04-02 1999-07-27 Pola Chemical Industries, Inc. Method for inducing apoptosis of cancer cell
JP2007230958A (en) * 2006-03-03 2007-09-13 Pola Chem Ind Inc Enhancer of radiosensitization ability in hypoxic cell radiosensitizer
JP2007302609A (en) * 2006-05-12 2007-11-22 Pola Chem Ind Inc Agent for reinforcing radiation-sensitizing ability in hypoxic cell radiation sensitizer
CN101642452A (en) * 2008-08-06 2010-02-10 株式会社宝丽制药 Radiation sensitizer used for brain tumor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BMC CANCER, vol. Vol. 13: 106, JPN6016040600, 8 March 2013 (2013-03-08) *

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