CN105963300B - The purposes of PIKfyve inhibitor Antiradiation injury - Google Patents
The purposes of PIKfyve inhibitor Antiradiation injury Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, the medical application about the Antiradiation injury purposes of PIKfyve inhibitor, mainly in its radiation injury caused by core/radiation injury prevention and treatment and tumour radiotherapy prevention and treatment.More particularly, the present invention prevents using PIKfyve inhibitor and/or treats various radiation injuries about individually or jointly other treatment methods.
Description
Technical field
The invention belongs to pharmaceutical technology fields, about the Antiradiation injury purposes of PIKfyve inhibitor, mainly it
Medical application in the prevention and treatment of radiation injury caused by core/radiation injury prevention and treatment and tumour radiotherapy.More particularly, originally
Invention prevents using PIKfyve inhibitor and/or treats various radiation damages about individually or jointly other treatment methods
Wound.
Background technique
The application of nuclear energy and nuclear technology in every field such as industrial and agricultural production, health care, scientific research and Defence business
Increasingly extensive, while bringing huge interests to the mankind, there is also potential threats for they.Nuclear war, relate to nuclear terror raid,
Shake or tsunami etc. cause nuclear power station occur in the work such as nuclear leakage and civilian radioactive source, medical exposure by poor management or
Operation error etc. all can lead to personnel by radiation exposure.When body is shone by large dosage of (> 1Gy) ionising radiation in a short time
Acute radiation sickness (Acute Radiation Sickness, ARS) can occur when penetrating, or be referred to as acute radiation injury syndrome
(Acute Radiation Syndrome disease,ARS).Acute radiation sickness is a kind of systemic disease, according to impaired device
The difference of official is divided into three type of BM form, visible peristalsis visible intestinal peristalsis and brain type；Acute, sub- urgency can be divided into according to by according to length of time difference radiation sickness
Property and chronic.The acute radiation sickness death rate is high, cures difficulty, and patient of the exposure dosage greater than 8Gy there is no the elder generation brought back to life at present
Example.In addition, tumor patient receives in radiation therapy process, ray also results in damage to normal cell while killing tumour cell
Therefore wound usually limits the practical application of radiotherapy.Therefore, in order to Antiradiation injury, to nuclear energy and nuclear technology
Efficient application provides safety guarantee, needs to greatly develop Antiradiation injury medical science.
Phosphatidylinositols -3- phosphoric acid 5- kinases (PIKfyve) is the lipid kinase of a 240kDa, can be specifically with intracellular
Phosphatidylinositols -3- the phosphoric acid (PI3P) of body is that substrate catalysis generates phosphatidylinositols -3,5- phosphoric acid (PI (3,5) P2).
PIKfyve and its PI of mediation (3,5) P2 signal path participate in maintaining intracellular inner body/lyase volume morphing, glucose transport, inverse
Retroviral budding, autophagy and ion channel activity etc..Research in nearly 2 years discloses PIKfyve in innate immune reaction
Important function can lower a variety of proinflammatory cytokines expression of TLR signal path mediation after PIKfyve activity suppression.Study table
Bright, PIKfyve inhibitor STA 5326 (STA) binds directly PIKfyve and inhibits its phosphate transferase activity, and then specificity resistance
The IL-12/IL-23 expression that disconnected Toll receptor (TLR) is mediated, and helper lymphocyte T subgroup Th1 type is inhibited to react.Due to
The critical role of immune system and inflammatory reaction in the acute radiation sickness course of disease, it is presumed that improvement inflammatory and immune response may be
The important channel for preventing and treating radiation injury.Based on this, we have discovered that 5326 He of PIKfyve specific inhibitor STA
YM201636 has significant preventive and therapeutic effect to Mice After Acute Irradiation Injury.This discovery still belongs to the first, and related content has not been reported.
To sum up, the present invention provides a kind of compound, that is, PIKfyve inhibitor Antiradiation injury purposes.
Summary of the invention
About the Antiradiation injury purposes of PIKfyve inhibitor, mainly it puts in core/radiation injury treatment and tumour
Penetrate the medical application in the prevention and treatment of radiation injury caused by treating.More particularly, the present invention is controlled about individually or jointly other
Various radiation injuries are prevented using PIKfyve inhibitor and/or treated to treatment method.
Inventor it has been investigated that: PIKfyve inhibitor is to bone marrow suppression caused by ionising radiation and associated
Disease has prevention and/or therapeutic effect.The present invention generates accordingly.
Specific discovery according to the present invention, provides
1. it is acute to treat for example slight bone marrow form acute radiation sickness of acute radiation sickness caused by a variety of causes, moderate BM form
Radiation sickness, ablative type acute radiation sickness, the method for Extremely severe bone marrow form of acute radiation sickness and visible peristalsis visible intestinal peristalsis radiation sickness, this method packet
Include the PIKfyve inhibitor for applying therapeutically effective amount before irradiation at least 1 day and/or after irradiation at least 1 day, such as hereafter institute
The compound 1 of definition is to compound 24.
2. the method for treating bone marrow suppression caused by radiation exposure, this method includes in irradiation is at least 1 day first and/or irradiating
The PIKfyve inhibitor of therapeutically effective amount, such as defined below 1 to 24 compound are applied at least 1 day afterwards.
3. the method for treating bone marrow suppression caused by tumour radiotherapy, this method includes at least 1 day, radiation before irradiation
During treating and/or at least 1 day after irradiation applies the PIKfyve inhibitor of therapeutically effective amount, such as defined below 1 to 24
Compound.
4. the method for treating bone marrow suppression caused by the radiotherapy carried out in conjunction with chemotherapy or surgical operation, should
Method includes at least 1 day before irradiation, during radiotherapy and/or after irradiation at least 1 day application therapeutically effective amount PIKfyve suppression
Preparation, compound 1 for example as defined below to compound 24.
These bone marrow suppressions are, include being ranked with the individual that PIKfyve inhibitor is treated and can be benefited by and large
Start or receiving radiotherapy.The individual that can especially benefit from this treatment includes having bone marrow suppression person or possible
Bone marrow suppression person easily occurs.For example, these individuals may to be ready receiving, may receive, or radiotherapy is received.
According to an aspect of the present invention, the method for bone marrow suppression caused by treating because of radiation includes, to needing these
The PIKfyve inhibitor of the individual dosage treatment effective amount for the treatment of.
In certain specific examples, PIKfyve inhibitor is administered at least one day before first dose of a body radiation therapy.
In some other specific examples, PIKfyve inhibitor arrives at least one day before first dose of radiotherapy of individual
Radiotherapy is administered in a period of at least one day after stopping.
In certain specific examples, before a body radiation therapy, first dose of chemotherapy at least by PIKfyve inhibitor
It is administered in one day.
Other specific examples include that PIKfyve inhibitor is administered during radiotherapy, chemotherapy.
PIKfyve inhibitor is usually amino-metadiazine compound, such as the compound of structure formula (I).
Wherein: X and Y be respectively containing 1-5 hetero atom replace C6-C20 alkyl, aryl, alkoxy, aryloxy group,
Or the amino replaced；W is the amino replaced, can connect cyclization with X, can also be not present；Z is alkoxy, substituted amino
Or the sulfydryl replaced, Z can connect cyclization with Y, can not also connect with Y；U is oxygen atom or methylene.
On the other hand, in which: X and Y can also be respectively containing 1-5 hetero atom replace alkyl, aryl, alkoxy,
Aryloxy group, or the amino replaced；W is the amino replaced, can connect cyclization with X, can also be not present；Z is alkoxy, is replaced
Amino or substituted sulfydryl；U is oxygen atom, methylene.
In another aspect, wherein X and Y is the alkyl of the C10-C16 replaced containing 1-5 hetero atom, alkoxy, virtue respectively
Base, or the amino replaced；W is the amino replaced, can connect cyclization with X, can also be not present；Z is hydrogen atom；U is that oxygen is former
Son.
Alternatively, wherein X and Y is the alkoxy of the C10-C16 replaced containing 1-5 hetero atom, aryl, or substitution respectively
Amino；W is the amino replaced, can connect cyclization with X, can also be not present；Z is hydrogen atom；U is oxygen atom.
Including but not limited to following compound 1 to compound 24 compound.
(E) -4- (6- (2- (3- chlorobenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine (chemical combination
Object 1)
(E) -4- (6- (2- (3- fluorobenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine (chemical combination
Object 2)
(E) -4- (6- (2- (3- allyl iodide diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine (chemical combination
Object 3)
(E) -4- ((change by 6- (2- (3- methylbenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine
Close object 4)
(E) -4- (6- (2- (3- bromobenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine (chemical combination
Object 5)
The bromo- N'- of 3- (6- morpholinyl -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine (compound 6)
3- methyl-N'- (6- morpholinyl -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine (compound
7)
3- methyl-N'- (6- morpholinyl -2- (2- (pyridine -2- base) ethylamino-) pyrimidine-4-yl) benzoyl hydrazine (compound
8)
3- methyl-N'- (6- morpholinyl -2- (phenyl ethylamine base) pyrimidine-4-yl) benzoyl hydrazine (compound 9)
N'- (6- morpholinyl -2- (phenyl ethylamine base) pyrimidine-4-yl) -3- pyridinecarboxylic hydrazine (compound 10)
N'- (6- morpholinyl -2- (phenyl ethylamine base) pyrimidine-4-yl)-Isoniazid (compound 11)
4- morpholinyl-N- phenethyl-pyridine [3', 2':4,5] furans [3,2-d] and pyrimidine -2- amine (compound 12)
N- (3- (4- morpholinyl-pyridine [3', 2':4,5] furans [3,2-d] and pyrimidine -2-base) phenyl) Buddhist nun can amide (change
Close object 13)
6- amino-N- (3- (4- morpholinyl-pyridine [3', 2':4,5] furans [3,2-d] and pyrimidine -2-base) phenyl) Buddhist nun can
Amide (compound 14)
(E) -4- (5- (2- (3- methylbenzene methene) diazanyl) -2- Phenylpyrazole simultaneously [1,5-a] pyrimidin-7-yl) morpholine
(compound 15)
(E) -4- (5- (2- (3- methylbenzene methene) diazanyl) -2- (4- pyridyl group) pyrazolo [1,5-a] pyrimidin-7-yl)
Morpholine (compound 16)
3- methyl-N'- (7- morpholinyl -2- (pyridin-4-yl) pyrazoles [1,5-a] pyrimidine -5- base) benzoyl hydrazine (compound
17)
The chloro- N'- of 3- (7- morpholinyl -2- (pyridin-4-yl) pyrazoles [1,5-a] pyrimidine -5- base) benzoyl hydrazine (compound
18)
(E) -4- (5- (2- (3- chlorobenzene methene) diazanyl) -2- (4- pyridyl group) pyrazolo [1,5-a] pyrimidin-7-yl)
Quinoline (compound 19)
The fluoro- N'- of 3- (7- morpholinyl -2- (pyridin-4-yl) pyrazoles [1,5-a] pyrimidine -5- base) benzoyl hydrazine (compound
20)
(E) -5- (2- (3- methylbenzene methene) hydrazine) -7- (piperidin-1-yl) -2- (pyridin-4-yl) pyrazoles [1,5-a] is phonetic
Pyridine (compound 21)
3- methyl-N'- (7- piperidin-1-yl -2- (pyridin-4-yl) pyrazoles [1,5-a] pyrimidine -5- base) benzoyl hydrazine (is changed
Close object 22)
(E) -4- ((change by 6- (2- (3- methylbenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) piperidines
Close object 23)
6- amino-N- (3- (4- piperidin-1-yl-pyridine [3', 2':4,5] furans [3,2-d] and pyrimidine -2-base) phenyl)
Buddhist nun can amide (compound 24)
It should be appreciated that compound described herein can be direct active material, or it can be prodrug.For example, compound
It can be the form of phosphorylation.
It is providing cited patent applications or scientific publications in each case, theme relevant to compound here by
It is incorporated herein as reference.Further include its officinal salt, corresponding racemate, diastereoisomer, enantiomter, mutually
Tautomeric and above compound corresponding crystalline modifications (in the presence of), for example, solvate, hydrate disclosed in it and
Polymorph.Can the description as quoted in document prepare and apply respectively the chemical combination for being used as active constituent in of the invention combine
Object.It further include the combination of two or more individual active constituents as shown above in the scope of the invention, i.e., in the scope of the invention
Pharmaceutical composition may include three kinds or more active constituents.In addition, the first activating agent and coagent be not it is identical at
Point.As used herein, administration preferably belong to take orally, drug administration by injection.
Specific embodiment
The method that this specification discloses prevention and/or treatment ionization radiation injury.
Have this need group include may will by radioactive exposure, such as first strike, the core dirty bomb attack of terrorism,
Or radiocontamination region will be entered, a few hours or at least 1 day receive a effective amount of PIKfyve suppression before (possibility) radioactive exposure
Preparation prophylactic treatment.
Individuals in need includes being subjected to the wounded or the accident disease of the exposure dose that may lead hematopoiesis damage
People, after Yu Shouzhao at once, a few hours or at least 1 day it is inscribed by a effective amount of PIKfyve inhibitor for treating.
This specification also discloses treatment because of the method for the bone marrow suppression caused by radiotherapy.
Radiotherapy (radiation therapy) and radiotherapy (radiotherapy) Yu Benwen are used interchangeably,
And including external exposure (external irradiation) and interior irradiation (internal irradiation), referred to as proximity is also referred to
Proximity between (brachytherapy), intracavitary brachytherapy (intracavitary brachytherapy), or tissue is treated to control
It treats (interstitial brachytherapy).The radioactive source that can be taken into account includes pure gamma (pure Gamma), pure beta
(pure Beta), and mixing radiation.
Used herein, term " chemotherapy " and " chemotherapeutant " are used interchangeably, and mean to show anticancer
Effect and the chemotherapeutant or medicine being used in the treatment of malignant tumour.
Used herein, radiating caused bone marrow suppression includes the offices such as full-body exposure or chest lung, pelvis, trunk
The caused radiation insult of portion's irradiation.Irradiation often results in acute radiation sickness or marrow hemopoiesis inhibits.Symptom may include vomiting, hematopoiesis
Leukopenia, anaemia, thrombopenia, leukopenia, hematopoietic cell proliferation obstacle, thrombocytopenic bleeding etc..
The present invention again another aspect about with PIKfyve inhibitor for treating individuals in need (for example, mammality, people
Class, horse, dog, cat) method.The demand whether confirmation individual has these to treat, can be special according to individual itself or health irradiation protection
The judge of industry personnel, and can be for subjective (for example, view) or objectively (for example, can be measured by test or diagnostic method
It surveys).
Individuals in need includes the individual that will receive radiotherapy, whether individually receives radiotherapy or combination
Other chemotherapys that can lead to bone marrow suppression.This needs may be revealed in individual receive radiotherapy, chemotherapy or
Before the combination of (several) treatments；Individual is receiving the combination of radiotherapy, chemotherapy or (several) treatments；Individual is
After the combination for receiving radiotherapy, chemotherapy or (several) treatments.For example, individual may be about to, may, or
Through receiving, radiation therapy in combination chemotherapy.
Used herein, therapeutically effective amount is it is meant that when administered to a human or non-human subject, effectively provide treatment benefit
The amount for locating (for example, improvement to symptom), for example, being effectively improved the amount of Anemia.
According to certain specific examples, PIKfyve inhibitor can be used for various therapeutic schemes, these schemes can according to individual and
It treats type and changes.
PIKfyve inhibitor can before treatment, period, and/or be administered later.For example, can be in the radiotherapy of individual
It is administered at least one day before first dose, is administered during radiotherapy, is administered at least one day after radiotherapy stopping.
PIKfyve inhibitor is preferably administered before myelosuppresive therapy, during treatment and after treatment.For example,
After stopping from least one day before radiotherapy, first dose of chemotherapy and combined treatment to radiotherapy, chemotherapy stops
It is administered in a period of at least one day after only.
According to particular embodiment, PIKfyve inhibitor is administered together in combination with other compounds, for example, chemotherapy
Agent, antiinflammatory agents, antipyretic, radiosensitizer, radioprotector, the urinary tract agent, antiemetic and/or antidiarrheic.For example,
Cis-platinum (cisplatin), carboplatin (carboplatin), Docetaxel (docetaxel), Paclitaxel
(paclitaxel), fluorouracil (flurouracil), capecitabine (capecitabine), gemcitabine
(gelncitabine), Irinotecan (irinotecan), Hycamtin (topotecan), Etoposide (etoposide),
Mitomycin (mitomycin), Gefitinib (geftinib), vincristine (vincristine), vincaleukoblastinum
(vinblastine), adriamycin (doxorubicin), cyclophosphamide (cyclophosphamide), celecoxib
(celecoxib), rofecoxib (rofecoxib), valdecoxib (valdecoxib), brufen (ibuprofen), naproxen
(naproxen), Ketoprofen (ketoprofen), dexamethasone (dexamethasone), prednisone (prednisone), bold and vigorous Buddhist nun
Song Long (prednisolone), hydrocortisone (hydrocortisone), acetaminophen (acetaminophen), misso stone Xiao
Azoles (misonidazole), Amifostine (amifostine), Tamsulosin (tamsulosin), phenazopyridine
(phenazopyridine), Ondansetron (ondansetron), Granisetron (granisetron), Alosetron
(alosetron), palonosetron (palonosetron), fenazil (promethazine), prochlorperazine
(prochlorperazine), trimethobenzamide (trimethobenzamide), aprepitant (aprepitant), it is fragrant
Promise ester adds atropine (diphenoxylate with atropine), Balsalazide (balsalizide) and/or Loperamide
(loperamide)。
The method disclosed herein, it is a to protect to the PIKfyve inhibitor of individuals in need dosage treatment effective amount
Body is also useful to systemic injury caused by anti-radiation.For example, preventative take can be before patient receives radiation
Administration.
Detailed description of the invention
Influence of the 1h stomach-filling to 8.5Gy gamma-rays full-body exposure C57 mouse survival before Fig. 1 .STA irradiates
The result shows that start within irradiation control group mouse the 10th day after irradiation to occur dead, none survival in two weeks, and
STA group mouse then occurs since the 14th talent dead, and 30 days whens survive 40%.
Influence of the 1h stomach-filling to 6.5Gy gamma-rays full-body exposure C57 mouse peripheral blood cell number before Fig. 2 .STA irradiates
The results show that 1h gives mouse single oral gavage STA5326 10,20 and 30mg/ before irradiating compared with irradiation control group
Kg can promote peripheral blood platelet count, red blood cell number to restore；And as dosage increases, which is presented enhancing
It is the most obvious to promote recovery effects with 30mg/kg group for trend
1h stomach-filling is to 6.5Gy gamma-rays full-body exposure C57 mouse peripheral blood cell number before Fig. 3 various dose STA irradiates
It influences
Compared with irradiation control group, irradiate before 1h give respectively C57 intragastric administration on mice 20mg/kg, 30mg/kg, 40mg/kg and
When 50mg/kg STA5326, each group mouse peripheral leukocytes restore trend without significant difference, but 30 and 40mg/kg administration group
The recovery trend of mouse peripheral blood blood platelet and red blood cell is almost the same and is substantially better than irradiation control group, 20mg/kg and 50mg/
Kg group and the difference of irradiation control group are unobvious.
Shadow of the different time stomach-filling to 6.5Gy gamma-rays full-body exposure C57 mouse peripheral blood cell number before Fig. 4 .STA irradiates
It rings
Interior single oral gavage STA 30mg/kg can promote the hematopoiesis of 6.5Gy gamma-rays full-body exposure mouse thin for 24 hours before irradiation
Born of the same parents restore, wherein most obvious to irradiate the function and effect of preceding 3h administration.
Influence of the 3h stomach-filling to 8.5Gy gamma-rays full-body exposure C57 mouse survival before Fig. 5 .STA irradiates
Compared with irradiation control group, STA5326 20mg/kg group mouse survival rate is without significantly improving, but mouse starts death
Time retardation；And STA 30mg/kg and 40mg/kg administration not only extend the time-to-live of dead mouse, but also 30 days survival rates
Improve 50% (irradiation control group 0).
Influence of the 3h stomach-filling to 6.5Gy gamma-rays full-body exposure C57 Bone Marrow Hematopoietic Stem Cells of Mice before Fig. 6 .STA irradiates
Single karyocyte quantity living in 3h marrow is apparently higher than irradiation control group to STA group mouse after irradiation；Point
Analyse Lin-c-kit+Sca-1-Cell and Lin-c-kit+Sca-1+Content shows, the number of 14 days STA group two kinds of cells after irradiation
Amount is above irradiation control group.
Shadow of the different time stomach-filling to 6.5Gy gamma-rays full-body exposure C57 mouse peripheral blood cell number after Fig. 7 .STA irradiation
It rings
The result shows that interior single oral gavage STA 30mg/kg can promote 6.5Gy gamma-rays full-body exposure small for 24 hours after irradiation
The hematopoietic cell of mouse restores, especially significant to the rush restitution of blood platelet and red blood cell number, wherein to be administered for 24 hours after irradiation
Group function and effect are most obvious.
The influence to 6.5Gy gamma-rays full-body exposure C57 mouse peripheral blood cell number is injected intraperitoneally in 3h before Fig. 8 .STA irradiates
As a result, it has been found that before 6.5Gy full-body exposure 3h to C57 mouse peritoneal injection STA5326 30mg/kg can be improved it is small
The minimum of mouse peripheral white blood cells, and promote the recovery of blood platelet and red blood cell number.
The influence to 8.5Gy gamma-rays full-body exposure C57 mouse survival is injected intraperitoneally in 3h before Fig. 9 .STA irradiates
The all death (irradiation control group) in 30 days after irradiation of 8.5Gy full-body exposure C57 mouse, and 3h is mono- before irradiation
Secondary intraperitoneal injection STA5326 30mg/kg can make the current deposit rate of mouse improve 90%.
Specific embodiment
Lethal exposure mouse survival rate can be improved in 1, the STA5326 preceding 1 hour single oral gavage of irradiation.
For the Study On The Radioprotective of preliminary observation STA5326, the male adult C57 mouse of health is divided into irradiation control group
With STA administration group, every group 10.The STA5326 (0.2ml/ mouse) of STA group mouse 1h single oral gavage 20mg/kg before irradiating, shines
Penetrate control group stomach-filling PEG400 0.2ml/ mouse.Mouse exposure dosage is60Co gamma-rays whole body once irradiating 8.5Gy irradiates agent
Dose rate is 61.6cGy/min, observes the survival condition of mouse after irradiation twice daily, is observed continuously 30 days.The result shows that irradiation
Start within control group mice the 10th day after irradiation to occur dead, none survival in two weeks, and STA group mouse then opens from the 14th talent
Begin to occur dead, 30 days whens survive 40% (Fig. 1).
2, STA5326 before irradiation 1 hour single oral gavage can promote Irradiated Mice hematopoietic cell recovery
After radiation exposure, body hematopoiesis function is damaged, and blood cell count is reduced rapidly, and leucocyte, platelet counts
Infection and hemorrhage complication caused by falling sharply usually cause patient dead, and the reduction of erythrocyte number and content of hemoglobin causes
Anaemia also can not be ignored.In order to observe influence of the STA to exposure body hematopoiesis function, we use 6.5Gy60Co gamma-rays one
Subtotal body irradiation (exposure dose rate 61.6cGy/min) C57 mouse establishes hemopoietic system damage model caused by acute exposure.It is small
Mouse is divided into irradiation control and totally four groups of STA10mg/kg, 20mg/kg and 30mg/kg, every group 8.Tri- administration group mouse of STA point
1h single oral gavage 10mg/kg, 20mg/kg and 30mg/kg STA5326 not before irradiation, irradiation control group stomach-filling 0.2ml/ mouse
PEG400.Different time takes tail vein to detect peripheral blood cells number after irradiation.The results show that compared with irradiation control group,
1h can promote the recovery of mouse peripheral blood cell to 10,20 and 30mg/kg of mouse single oral gavage STA5326 before irradiating, especially
It is that human peripheral blood platelet count, the rush restitution of red blood cell number are significant；And as dosage increases, which is presented
It is the most obvious (Fig. 2) to promote haemocyte recovery effects with 30mg/kg group for the trend of enhancing.
3, the STA5326 of various dose influence of 1 hour single oral gavage to Irradiated Mice Radiation in jury before irradiation
The STA5326 for further looking at various dose is administered in the preceding single oral gavage of irradiation to 6.5Gy60Co gamma-rays whole body
Irradiate the influence that (exposure dose rate 60.0cGy/min) mouse hematopoetic cell restores.Experiment discovery, compared with irradiation control group,
When 1h gives C57 mouse (n=8) stomach-filling 20mg/kg, 30mg/kg, 40mg/kg and 50mg/kg STA5326 respectively before irradiating, respectively
Group mouse peripheral leukocytes restore trend without significant difference, but 30 and 40mg/kg administration group mouse peripheral blood blood platelet and red
The recovery trend of cell is almost the same and is substantially better than irradiation control group, the difference of 20mg/kg and 50mg/kg group and irradiation control group
Different unobvious (Fig. 3).
4, STA5326 influences of the different time prevention administration to Irradiated Mice Radiation in jury before irradiation
On above-mentioned experiment basis, with 6.5Gy60Co gamma-rays full-body exposure (exposure dose rate 60.0cGy/min) mouse
For model, observes STA different time before irradiation and the influence to irradiated mice Radiation in jury is administered.C57 mouse is divided into
Irradiation control and STA administration group, wherein the administration time of STA be set to before irradiation for 24 hours (- for 24 hours), irradiate before 12h (- 12h),
3h (- 3h) and preceding totally 4 groups, every group 8 of the 1h (- 1h) of irradiation before irradiating.Corresponding time single fills STA administration group before irradiation respectively
Stomach STA5326 30mg/kg (0.2ml/ mouse), the PEG400 of irradiation control group stomach-filling 0.2ml/ mouse.It is thin to detect mouse peripheral blood
Born of the same parents, the results showed that, interior single oral gavage STA 30mg/kg can promote making for 6.5Gy gamma-rays full-body exposure mouse for 24 hours before irradiation
Haemocyte restores, wherein most obvious (Fig. 4) to irradiate the function and effect of preceding 3h administration.
5, STA5326 before irradiation 3h single oral gavage administration significantly improve lethal dose irradiation mouse survival rate
It is observed in above-mentioned experiment extensive to irradiated mice hemopoietic system to irradiate 3h administration when STA is administered before irradiation
Multiple facilitation is the most obvious, in order to confirm the Study On The Radioprotective of STA, this Germicidal efficacy 8.5Gy60Co gamma-rays (shines
Penetrate dosage rate 60.0cGy/min) before full-body exposure 3h to C57 mouse gavage respectively STA5326 20mg/kg, 30mg/kg and
40mg/kg (n=10) observes 30 days survival conditions of mouse.As shown in figure 5, compared with irradiation control group, STA5326
20mg/kg group mouse survival rate is without significantly improving, but mouse starts death time postponement；And STA 30mg/kg and 40mg/kg give
Medicine not only extends the time-to-live of dead mouse, but also 30 days survival rates improve 50% (irradiation control group 0).
6, STA5326 influences of the 3h single oral gavage administration to Irradiated Mice marrow hemopoietic stem cells before irradiation
It is extensive to have been demonstrated that STA5326 3h single oral gavage administration before irradiation can remarkably promote Irradiated Mice hematopoietic cell
It is multiple, and the survival rate of lethal dose irradiation mouse can be improved.Based on this, we have further looked at STA5326 prevention administration pair
The influence of Irradiated Mice candidate stem cell.The male C57 of 40 healthy adults is divided for irradiation control group and STA group, every group
20.STA group mouse 3h single oral gavage STA5326 30mg/kg (0.2ml/ mouse) before irradiating, irradiation control group gavages
PEG4000.2ml/ mouse.Mouse receives 6.5Gy60Co gamma-rays full-body exposure.Difference 3 hours, 1,10 and 14 day after irradiation
5 mouse of every group of execution collect femur bone marrow cell, after marking cell with Lin FITC, c-kit APC and Sca-1PE-Cy7
With the content of hematopoietic stem/progenitor cells in flow cytomery bone marrow cell.As shown in fig. 6, STA group mouse 3h bone after irradiation
Single karyocyte quantity living is apparently higher than irradiation control group in marrow；Analyze Lin-c-kit+Sca-1-Cell and Lin-c-
kit+Sca-1+Content shows, the quantity of 14 days STA group two kinds of cells is above irradiation control group after irradiation.Should the result shows that,
Administration can not only protect Irradiated Mice bone marrow cell before STA irradiation, moreover it is possible to convalescence candidate stem cell be stimulated to generate.
7, STA5326 influences of the different time single oral gavage administration to Irradiated Mice Radiation in jury after irradiation
After specifying that STA is administered before irradiation and has apparent protective action to Mice After Acute Irradiation Injury, further to grind
Study carefully STA and be administered that whether there is or not therapeutic effects to acute radiation injury after irradiation, by 6.5Gy60Co gamma-rays full-body exposure (irradiation agent
Dose rate 60.0cGy/min) C57 mouse is divided into irradiation control group and STA treatment group, wherein STA group be divided into 1h (+1h) after irradiation,
3h (+3h) after irradiation, after irradiation after 12h (+12h), irradiation for 24 hours (+for 24 hours).The corresponding time is single after irradiation respectively for STA administration group
Secondary stomach-filling STA5326 30mg/kg (0.2ml/ mouse), the PEG400 of irradiation control group stomach-filling 0.2ml/ mouse.Detect mouse peripheral blood
As the result shows that, after irradiation for 24 hours in single oral gavage STA 30mg/kg can promote making for 6.5Gy gamma-rays full-body exposure mouse
Haemocyte restores, especially significant to the rush restitution of blood platelet and red blood cell number, wherein with administration group acts on for 24 hours after irradiation
Effect is most obvious (Fig. 7).
8, STA5326 before irradiation the administration of 3 hours single intraperitoneal injections can promote Irradiated Mice Radiation in jury, and make to cause
Dead dosage irradiation mouse current deposit rate improves 90%.
The studies above find STA before irradiation and irradiation after gastric infusion can not only promote irradiate mouse hemopoietic function it is extensive
It is multiple, the survival rate of lethal dose irradiation mouse is also significantly improved, the time-to-live is extended.The administration mode of STA is changed in this experiment
Its Radioprotective Effect to mouse is further looked at for intraperitoneal injection.As a result, it has been found that 3h is small to C57 before 6.5Gy full-body exposure
The minimum of mouse peripheral blood leucocyte can be improved in mouse intraperitoneal injection STA5326 30mg/kg, and promotes blood platelet and red thin
The recovery (Fig. 8) of born of the same parents' number.Prompt, STA intraperitoneal injection equally have Study On The Radioprotective to the hemopoietic system of mouse.With
8.5Gy lethal dose irradiation mouse is that the result of study of model is shown, 3h single intraperitoneal injection STA5326 30mg/kg before irradiating
The current deposit rate of mouse can be made to improve 90% (Fig. 9).
Claims (1)
1.PIKfyve inhibitor is following anyization preparing the application in antiradiation injury medicine, the PIKfyve inhibitor
Close object:
(E) -4- (6- (2- (3- chlorobenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine
(E) -4- (6- (2- (3- fluorobenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine
(E) -4- (6- (2- (3- allyl iodide diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine
(E) -4- (6- (2- (3- methylbenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine
(E) -4- (6- (2- (3- bromobenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) morpholine
The bromo- N'- of 3- (6- morpholinyl -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine
3- methyl-N'- (6- morpholinyl -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine
3- methyl-N'- (6- morpholinyl -2- (2- (pyridine -2- base) ethylamino-) pyrimidine-4-yl) benzoyl hydrazine
3- methyl-N'- (6- morpholinyl -2- (phenyl ethylamine base) pyrimidine-4-yl) benzoyl hydrazine
N'- (6- morpholinyl -2- (phenyl ethylamine base) pyrimidine-4-yl) -3- pyridinecarboxylic hydrazine
N'- (6- morpholinyl -2- (phenyl ethylamine base) pyrimidine-4-yl)-Isoniazid
(E) -4- (6- (2- (3- methylbenzene alkene diazanyl) -2- (2- (pyridine -2- base) ethyoxyl) pyrimidine-4-yl) piperidines
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