Use of PD173074 in preparing medicament for relieving itch or pruritus

Abstract

Disclosed is the use of and a medicament comprising N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-D]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea, hereinafter referred to as PD173

Description

USE OF PD173074 IN PREPARING MEDICAMENT FOR RELIEVING ITCH OR PRURITUS TECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of medicine, and particularly relates to use of PD173074 in preparing a medicament for relieving itch or pruritus. BACKGROUND

[0002] Itch or pruritus is an unpleasant sensation that triggers an urge to scratch, and the pathogenesis thereof is closely related to the nervous, endocrine, and immune systems. Normal itch or pruritus is a protective response of the body to skin irritation. However, long-term itch or pruritus can cause problems of sleep deprivation, anxiety and depression and seriously affect the quality of life. Not only can the itch or pruritus occur alone (for example, skin pruritus common in the elderly, which is mainly manifested as pruritus, without obvious primary lesions), but it is also a concomitant symptom of other diseases. The current research showed that a plurality of cells in the epidermis or dermis was involved in the pathogenesis of itch or pruritus. In the damaged skin tissue, keratinocytes, T and B lymphocytes, mast cells, basophils, eosinophils, and fibroblasts produce substantial cytokines and inflammatory mediators associated with itch or pruritus, for example, interleukin 4 (IL-4), IL-6, IL-17, IL-22, IL-31, IL-33, cysteine and serine proteases, nerve growth factor (NGF), neuropeptide, substance P, calcitonin gene related peptide, endothelin, 5-hydroxytryptamine, leukotriene, and prostaglandin. These molecules serve as potential targets for the research on the mechanism of injury-induced itching and the intervention treatment. It is now believed that the pathogenesis of itch or pruritus is mainly involved in histamine-dependent and histamine-independent signaling pathways. However, the existing anti-histamine drugs have poorer outcomes of chronic itch or pruritus and more side effects. Therefore, effects of histamine-independent inhibitors on itch or pruritus are noteworthy.

[0003] Fibroblast growth factors (FGFs) can be classified into paracrine and endocrine subfamilies. The paracrine FGFs bind to heparin-sulfate proteoglycans, and the endocrine FGFs bind to Klotho family transmembrane proteins, both of which bind to fibroblast growth factor receptors (FGFRs). FGFRs subtypes include FGFR1, FGFR2, FGFR3, and FGFR4, which belong to the members of the receptor tyrosine kinases (RTKs) superfamily. FGFRs activate RAS-ERK, PI3K-AKT, and DAG-PKC signaling pathways to participate in the proliferation, differentiation, and epithelial-mesenchymal transition of normal cells through FRS2a and PLC pathways. In addition, FGFs and FGFRs may also serve as oncogenes to drive the tumor cell proliferation and participate in the pathogenesis of a plurality of types of tumors, being hotspot targets for the research and development of antitumor drugs. In recent years, intracellular signaling pathways mediated by FGFs and FGFRs are attracting much more attention in terms of inflammation immunity and tissue injury repair.

[0004] N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-D]pyrimidin-7 -yl]-N-(1,1-dimethylethyl)urea (hereinafter referred to as PD173074) is an ATP competitive FGFR1 inhibitor that inhibits FGFR1 phosphorylation in a dose-dependent manner and has an ICso in the range of 1 to 5 nM. In vitro cell experiments indicated that PD173074 inhibited neurite outgrowth and antagonized the proliferation and differentiation of oligodendrocytes. / n vivo experiments in mice indicated that PD173074 inhibited the neovascularization and significantly delayed the tumor growth. However, there is no definite report on whether the FGFRI1 antagonist PD173074 can be used to treat itch or pruritus. SUMMARY

[0005] In view of this, an objective of the present disclosure is to provide use of PD173074 in preparing a medicament for relieving itch or pruritus.

[0006] To achieve the above objective, the present disclosure provides the following technical solutions:

[0007] The present disclosure provides use of PD173074 in preparing of a medicament for relieving itch or pruritus.

[0008] Preferably, the itch or pruritus may include surgical incision-induced itch or pruritus.

[0009] Preferably, the itch or pruritus may include bleomycin-induced itch or pruritus.

[0010] Preferably, an effective dose of the PD173074 may be in the range of 10 pg / kg to 100 mg / kg.

[0011] The present disclosure further provides a medicament for relieving itch or pruritus, and an active ingredient of the medicament includes PD173074.

[0012] Preferably, the medicament may include an injection, an emulsion, and an ointment.

[0013] Preferably, a content of the PD173074 in the medicament may be 0.1-99wt%.

[0014] Preferably, the medicament may further include pharmacologically acceptable carriers.

[0015] The present disclosure has the following beneficial effects:

[0016] The present disclosure first sets forth use of PD173074 in preparing a medicament for relieving itch or pruritus. By constructing a surgical incision-induced itch model and a bleomycin-induced itch model, the present disclosure finds that the PD173074 can effectively inhibit the itching behaviors of mice in both models, indicating that the PD173074 has an inhibitory effect on the itch or pruritus. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 illustrates inhibitory effects of different experimental groups on surgical incision-induced itching behaviors in mice;

[0018] FIG. 2 illustrates inhibitory effects of different experimental groups on bleomycin (BLM)-induced itching behaviors. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0019] The present disclosure provides use of PD173074 in preparing a medicament for relieving itch or pruritus.

[0020] The PD173074 provided by the present disclosure is an ATP competitive FGFR1 inhibitor. The present disclosure has no particular limitation on specific sources of the PD173074, as long as a commercially available product conventional in the art may be used.

[0021] In the present disclosure, the itch or pruritus may include surgical incision-induced itch or pruritus, and further include bleomycin-induced itch or pruritus. Through intraperitoneal injection into mice in a surgical incision-induced itch model or a bleomycin-induced itch model, the present disclosure finds that the PD173074 can effectively inhibit itching behaviors of mice in both models.

[0022] In the present disclosure, an effective dose of the PD173074 may be in the range of 10 ug / kg to 100 mg / kg, and preferably 100 pg / kg to 50 mg / kg.

[0023] The present disclosure further provides a medicament for relieving itch or pruritus, and an active ingredient of the medicament includes PD173074. For the active ingredient of the medicament for relieving itch or pruritus provided by the present disclosure, the PD173074 may be used as the only active ingredient, or the PD173074 may be used in combination with other active ingredients having an inhibitory effect of the itch or pruritus.

[0024] In the present disclosure, the medicament may include but are not limited to an injection, an emulsion, and an ointment. In the present disclosure, the medicament may further include pharmacologically acceptable carriers. The present disclosure has no particular limitation on other excipients contained in the medicament, as long as pharmaceutical excipients common in the art may be used.

[0025] In the present disclosure, a content of the PD173074 in the medicament may be 0.1-99.9wt%, preferably 10-80wt%, and more preferably 17-73wt%.

[0026] The technical solutions provided by the present disclosure will be described in detail below with reference to examples, but they should not be construed as limiting the claimed scope of the present disclosure.

[0027] In the following examples, all methods are conventional methods, unless otherwise specified.

[0028] All materials and reagents used in the following examples may be commercially available, unless otherwise specified.

[0029] Example 1

[0030] The PD173074 provided by the present disclosure had an inhibitory effect on surgical incision-induced itch.

[0031] C57 mice (weighing 20-30 g) were anesthetized with 4% isoflurane. A 0.5 cm incision was made in the right cheek using a sterile surgical blade, and itching behavior was measured after 6 h. The itching behavior was specifically measured according to the following steps: the mouse that received incision treatment was placed in a transparent plastic mouse behavioral box, and the number of scratches of the mouse was recorded using a high-definition camera, during which the room was kept quiet. One scratch was defined as a lifting of the hind limb to touch the itching site and then a replacing of the limb back to the floor or in the mouth. The number of scratches within 30 min was counted. Each group was recorded 10 min after intraperitoneal injection. Six mice were included in each group.

[0032] Experiment 1:

[0033] The control group was Incision + Vehicle (the vehicle was 0.9% normal saline, with a volume of 20 uL); and

[0034] the experimental group was Incision + PD173074 (1 mg / kg, HY-10321, MCE, Inc., dissolved in 0.9% normal saline, with a volume of 20 pL).

[0035] Experiment 2:

[0036] The control group was Incision + Vehicle (the vehicle was 0.9% normal saline, with a volume of 20 pL); and

[0037] the positive drug 1 group was Incision + Bilastine (5 mg / kg, HY-14447, MCE, Inc., dissolved in 0.9% normal saline, with a volume of 20 pL).

[0038] Experiment 3:

[0039] The control group was Incision + Vehicle (the vehicle was 0.9% normal saline, with a volume of 20 pL); and

[0040] the positive drug 2 group was Incision + PD176252 (5 mg / kg, 204067-01-6, TOCRIS, Inc., dissolved in 0.9% normal saline, with a volume of 20 uL).

[0041] The results are shown in Table 1 and FIG. 1.

[0042] Table = The inhibitory effects of different experimental groups on surgical incision-induced itching behaviors in mice Experimental Number of scratches | Inhibition Traatmant Pua: Treatment I I Pvalue group (Mean = SEM) rate Incision + Vehicle 66+17.1 i ANCISION + VEGI Experimental . Teor) crtmwe le Incision + group 1 I 236.7 P<0.05 65% PD173074 Incision + Vehicle 51+£10.7 Experimental | Incision + Vehicle group 2 Incision + Bilastine 23£20 P<0.05 55% Incision + Vehicle 74+ 18.6 § ACISION T VOIILIC Experimental . Tort ed mon 1 Incision + group 3 48+ 13.8 P>0.05 35% PD176252

[0043] As can be seen from Table 1 and FIG. 1, compared with the control group, PD173074 significantly inhibits the surgical incision-induced itching behavior, with an inhibition rate of 65% (A of FIG. 1). Positive drug 1 (a compound for inhibiting histamine-dependent itch: histamine H1 receptor blocker Bilastine) significantly inhibits the surgical incision-induced itching behavior, with an inhibition rate of 55% (B of FIG. 1); positive drug 2 (a compound for inhibiting histamine-independent itch: bombesin receptor antagonist PD176252) cannot significantly inhibit the surgical incision-induced itching behavior, with an inhibition rate of 35% (C of FIG. 1). It is indicated that the PD173074 provided by the present disclosure has a significant inhibitory effect on surgical incision-induced itch and has a higher inhibition rate than the existing positive drugs.

[0044] Example 2

[0045] The PD173074 provided by the present disclosure had an inhibitory effect on bleomycin-induced itch.

[0046] C57 mice (weighing 20-30 g) were anesthetized with 4% isoflurane. The right cheek of mice were subcutaneously injected with bleomycin (BLM, 50 ug / 20 pL, HY-17565A, MCE, Inc.) once every other day, for five consecutive weeks to measure the itching behavior. The itching behavior was specifically measured according to the following steps: the mouse was placed in a transparent plastic mouse behavioral box, and the number of scratches of the mouse was recorded using a high-definition camera, during which the room was kept quiet. One scratch was defined as a lifting of the hind limb to touch the itching site and then a replacing of the limb back to the floor or in the mouth. The number of scratches within 30 min was counted. Each group was recorded 10 min after intraperitoneal injection. Six mice were included in each group.

[0047] Experiment 1:

[0048] The control group was BLM + Vehicle (the vehicle was 0.9% normal saline, with a volume of 20 pL); and

[0049] the experimental group was BLM + PD173074 (1 mg / kg, HY-10321, MCE, Inc, dissolved in 0.9% normal saline, with a volume of 20 pL).

[0050] Experiment 2:

[0051] The control group was BLM + Vehicle (the vehicle was 0.9% normal saline, with a volume of 20 pL); and

[0052] the positive drug 1 group was BLM + Bilastine (5 mg / kg, HY-14447, MCE, Inc., dissolved in 0.9% normal saline, with a volume of 20 pL).

[0053] Experiment 3:

[0054] The control group was BLM + Vehicle (the vehicle was 0.9% normal saline, with a volume of 20 pL); and

[0055] the positive drug 2 group was BLM + PD176252 (5 mg / kg, 204067-01-6, TOCRIS, Inc., dissolved in 0.9% normal saline, with a volume of 20 pL).

[0056] The results are shown in Table 2 and FIG. 2.

[0057] Table 2 The inhibitory effects of different experimental groups on BLM-induced itching behaviors EE Number of Experimental ~ oo Inhibition Treatment scratches P value group Co IN rate Mean + S.E.M) Experimental BLM + Vehicle 60+12.3 group 1 BLM + PD173074 14x59 P<0.01 77% Experimental BLM + Vehicle 61+13.4 group 2 BLM + Bilastine 27+6.2 P<0.05 56% Experimental BLM + Vehicle 5453 group 3 BLM + PD176252 2414 P<0.001 56%

[0058] As can be seen from Table 2 and FIG. 2, compared with the control group, PD173074 significantly inhibits the BLM-induced itching behavior, with an inhibition rate of 77% (A of FIG. 2). Positive drug 1 (a compound for inhibiting histamine-dependent itch: histamine H1 receptor antagonist Bilastine) significantly inhibits the BLM-induced itching behavior, with an inhibition rate of 56% (B of FIG. 2); positive drug 2 (a compound for inhibiting histamine-independent itch: bombesin receptor antagonist PD176252) significantly inhibits the BLM-induced itching behavior, with an inhibition rate of 56% (C of FIG. 2). It is indicated that the PD173074 provided by the present disclosure has a significant inhibitory effect on BLM-induced itching behavior and has a higher inhibition rate than the existing positive drugs.

[0059] The above descriptions are merely preferred embodiments of the present disclosure. It should be noted that a person of ordinary skill in the art may further make several improvements and modifications without departing from the principle of the present disclosure, but such improvements and modifications should be deemed as falling within the claimed scope of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. PD173074 for use in the treatment of an itch or pruritus.

2. PD173074 for use in the treatment of an itch or pruritus according to claim 1, wherein the itch or pruritus comprises surgical incision-induced itch or pruritus.

3. PD173074 for use in the treatment of an itch or pruritus according to claim 1, wherein the itch or pruritus comprises bleomycin-induced itch or pruritus.

4. PD173074 for use in the treatment of an itch or pruritus according to claim 1, wherein an effective dose of the PD173074 is between 10 pg / kg to 100 mg / kg.

5. A medicament for use in the treatment of an itch or pruritus, wherein an active ingredient of the medicament comprises PD173074.

6. The medicament according to claim 5, wherein the medicament comprises an injection, an emulsion, or an ointment.

7. The medicament according to claim 5 or 6, wherein a content of the PD173074 in the medicament is 0.1-99wt%.

8. The medicament according to claim 5 or 6, wherein the medicament further comprises pharmacologically acceptable carriers.

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