LU505115B1 - Medical use of pf429242 for protecting cerebral ischemia-reperfusion injury - Google Patents
Medical use of pf429242 for protecting cerebral ischemia-reperfusion injury Download PDFInfo
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- LU505115B1 LU505115B1 LU505115A LU505115A LU505115B1 LU 505115 B1 LU505115 B1 LU 505115B1 LU 505115 A LU505115 A LU 505115A LU 505115 A LU505115 A LU 505115A LU 505115 B1 LU505115 B1 LU 505115B1
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- cerebral ischemia
- reperfusion injury
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- 201000006474 Brain Ischemia Diseases 0.000 title claims abstract description 28
- 206010008120 Cerebral ischaemia Diseases 0.000 title claims abstract description 28
- 206010008118 cerebral infarction Diseases 0.000 title claims abstract description 28
- 206010063837 Reperfusion injury Diseases 0.000 title claims abstract description 22
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- 239000003814 drug Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
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- 238000002360 preparation method Methods 0.000 claims abstract description 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Chemical & Material Sciences (AREA)
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- Urology & Nephrology (AREA)
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Abstract
The present disclosure discloses medical uses of PF429242 for protecting ischemia-reperfusion injury. Specifically, the present disclosure provides uses of PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof in screening and preparation of a drug for preventing and/or treating cerebral ischemia-reperfusion injury. Through a lot of experiments, PFPF429242, as well as the enantiomers and racemates or pharmaceutically acceptable salts thereof are proved to effectively reduce brain injury and dysfunctions caused by rat cerebral ischemia-reperfusion injury, and have obvious protection effect on neurobrain cells.
Description
BL-5757
MEDICAL USE OF PF429242 FOR PROTECTING CEREBRAL LUS05115
ISCHEMIA-REPERFUSION INJURY
[0001] The present disclosure relates to a medical use of PF429242 particularly to medical uses of PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof, belonging to the technical field of medicines.
[0002] A cerebrovascular disease is one of three diseases leading to human death due to high incidence, disability and mortality, which seriously harms human health. So far, the primary treatment principle for cerebrovascular diseases in clinical practice is to restore or rebuild blood reperfusion as soon as possible, so that ischemic brain tissue can regain oxygen supply and provide necessary nutrients for metabolism and clear metabolites. On the one hand, these treatment measures can enable occluded cerebral blood vessels and ischemic brain tissues to be timely reperfused, thereby saving a large number of dying brain cells and facilitating the recovery of neuronal functions; On the other hand, ischemia-reperfusion of tissues often causes further exacerbation or even irreversibility of pathological damage, leading to worsening clinical symptoms. Such the phenomenon of further brain cell damage and dysfunctions caused after restoring blood flow perfusion is called cerebral ischemia-reperfusion injury, and weakening or eliminating reperfusion injury is a key to treat cerebral ischemic diseases.
[0003] So far, many researchers have done a lot of works on how to prevent and treat related diseases caused by cerebral ischemia, but there are few of drugs that can achieve expected therapeutic effects.
[0004] The man objective of the present disclosure is to provide medical uses of
PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof in screening and preparation of a drug for preventing and/or treating cerebral ischemia-reperfusion injury, in order to overcome the defects in the prior art.
[0005] A lot of experiments prove that PFPF429242 as well as the enantiomers and racemates or pharmaceutically acceptable salts thereof can effectively reduce brain cell 1
BL-5757 injury and dysfunction when cerebral ischemia-reperfusion in rats, and have a significant | LU505115 protective effect on neural brain cells, thus completing the present disclosure.
[0006] One aspect of an embodiment of the present disclosure provides uses of
PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof in preparation of a drug for preventing and/or treating cerebral ischemia-reperfusion injury.
[0007] Another aspect of an embodiment of the present disclosure further provides
PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof in screening of a drug for preventing and/or treating cerebral ischemia-reperfusion injury.
[0008] Further, the preventing and/or treating cerebral ischemia-reperfusion injury is inhibition or alleviation of the occurrence and/or progress of cerebral ischemia-reperfusion injury and/or reversion of pathologic change.
[0009] Further, the drug is a composition comprising PFPF429242 as well as enantiomers and racemates or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier or excipient.
[0010] The composition can be present as multiple formulation forms, for example injections, tablets, powders, etc., and is not limited thereto.
[0011] Yet aspect of an embodiment of the present disclosure further provides a pharmaceutical composition having a function of preventing and/or treating cerebral ischemia-reperfusion injury, comprising:
[0012] At least one of PFPF429242 and its enantiomers and/or at least one of pharmaceutically acceptable salts; and optionally a pharmaceutically acceptable carrier or excipient.
[0013] Further, the pharmaceutical composition comprises an equimolar mixture of
PF429242 and its enantiomers, that is, racemates of PF429242 (also known as a racemic composition).
[0014] PF429242 described in this specification is also called PF-429242 which has the following structural formula: 2
BL-5757
[0015] In the prior art, PF429242 mainly serves as a reversible competitive inhibitor of | LU505115 sterol regulatory element binding protein (SREBP) site 1 protease, that is, an S1P inhibitor, which has no significant inhibitory effect on trypsin, elastase, protease K, cytoplasmic reticulum, kallikrein, factor XIa, thrombin, or Flynn protease, but only a moderate inhibitory effect on urokinase and factor Xa. But so far, there have been no reports on a relationship between PF429242 and cerebral ischemia-reperfusion injury.
[0016] Further, the enantiomer of PF429242 is a left-handed chiral isomer of PF429242, which has the following structural formula:
O oY
N N zo
HN
(-)-PF429242 .
[0017] Further, the racemate of PF429242 is as follows
O
10h
N A zo
HN
(+/-)-PF429242
[0018] The “pharmaceutically acceptable salts” of the present disclosure can be specifically listed as salts formed by PF429242 or its enantiomers with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, or with organic acids such as formic acid, acetic acid, methanesulfonic acid, and ethanesulfonic acid, but are not limited to thereto. Further, the pharmaceutically acceptable salt of at least one of PF429242 or its enantiomers is preferably a water-soluble salt, particularly preferably hydrochloride.
[0019] In order to more clearly illustrate the embodiments or technical solutions in the present application, a brief introduction will be given to the accompanying drawings required in the embodiments or description of the prior art. It is evident that the accompanying drawings in the following description are only some of the embodiments recorded in the present application. For ordinary technical personnel in the art, other accompanying drawings can be obtained based on these drawings without any creative 3
BL-5757 effort. LU505115
[0020] FIG. 1A-FIG. 1D are laser speckle blood flow imaging photos of sham surgery group, control group, model group, and experimental group in an embodiment of the present disclosure.
[0021] FIG. 2A-FIG. 2D are Nissl staining photos of sham surgery group, control group, model group, and experimental group in an embodiment of the present disclosure.
[0022] Next, the embodiments of the present disclosure will be described in detail in combination with examples, however, those skilled in the art will understand that the following examples are only intended to illustrate the present disclosure and should not be considered as limiting the scope of the present disclosure. If specific conditions are not specified in the implementation example, the conventional conditions or manufacturer's recommended conditions shall be followed. The reagents or instruments used without specifying the manufacturer are all conventional products that can be obtained through market procurement.
[0023] This example adopts a four vessel method for global cerebral ischemia-reperfusion model, and pathological morphological analysis of neural brain cells is performed by using
Nissl staining in hippocampal CA1 area. The behavior and motor ability of rats are scored by an open field test to evaluate their behavioristics, neurological functions are scored by
Lemay method (see Table 1), and Nimodipine is used as a standard control drug.
Table 1 Score standard of neurological functions
Symptom and sign Stroke index/score Symptom and sign Stroke index/score
TE Siow movement or due 1
Enhanced ear contact response { Head raised 3
Keep eyes open 3 Blepharoptosis i
Extend hind limbs 3 Go Round 3 outward and backward
Convulsions or clonus 3 Limb weakness 5
Total score 25
Mild cerebral ischemia score 30 Severe cerebral ischemia score 38
[0024] 1. Experimental animals and grouping
[0025] 48 clean-grade healthy male SD adult rats (provided by Experimental Animal
Center of Xuzhou Medical University) were fed freely with water in an SPF environment and subjected to adaptive breeding for 48 hours. Experimental rats were randomly divided 4
BL-5757 into 4 groups (12 rats in each group): sham surgery group, model group, control group and | LU505115 experimental group.
[0026] 2. Establishment of full cerebral ischemia-reperfusion rat model
[0027] (1) Establishment of rat model
[0028] GCIR is a model for studying on recovery of a relative ideal state after ischemic injury. In this example, a full cerebral ischemia-reperfusion rat model was established by using Pulsinelli four-vessel method. The four-vessel occlusion method mainly is to separate bilateral common carotid arteries from an incision in the anterior midline of the neck, expose the first cervical transverse process wing and find the left and right transverse process foramen, and electrocoagulate the bilateral vertebral arteries, resulting in permanent occlusion. After 24 hours, medication pretreatment was carried out, the incision in the anterior midline of the neck was opended, and both common carotid arteries were ligated with arterial clamps to block blood for 15 min. The successful reference criteria of model: (1) loss of animal consciousness within 1 min after bilateral carotid artery occlusion; (2) eyeball enlargement, bilateral pupil dilation, disappearance of light reflex; (3) the righting reflex disappears. Any failure to meet the above standards or abnormal reactions such as systemic rigidity, convulsions, or death during reperfusion shall be considered as unsuccessful model establishment.
[0029] (2) Administration pretreatment
[0030] In this example, ail vein injection (0.1 ml/rat) was used to dissolve the drug with biological grade DMSO: physiological saline=1:1, and the drug was evenly dissolved by ultrasound for 5 min. Sham surgery group did not undergo ischemia or administration treatment, while model group (ischemia for 15 min and reperfusion) did not undergo medication pretreatment; control group (nimodipine, 0.51 mg/kg); experimental group (PF429242, 0.5 mg/kg).
[0031] 3. Neurological deficit score
[0032] After the surgery was ended and animals were completely awake, the first behavioral score was immediately performed, and were scored once again after 48 hours.
Rats with full cerebral ischemia were scored according to Lemay method grading criteria.
[0033] After 48 hours of reperfusion, the neurological deficit score of rats showed significant changes in the neural behavior of the rat full cerebral ischemia model in model group. Compared with sham operation group, there is statistically significant difference (Z=37.50, P<0.05), indicating successful modeling, by comparing model group with experimental group, there is statistically significant difference (Z=11.81, P<0.05),
BL-5757 indicating that administration treatment of PF429242 has a positive effect on rat | LU505115 reperfusion injury neural functions; by comparing nimodipine group and administration group, there is no statistically significant difference (Z=-1.09, P>0.05), indicating that there is no significant difference in the improvement of neural behavior in rats between the two groups.(See Table 2)
[0034] 4. Survival rate of rats
[0035] After 5 days, the survival rate of rats in each group was calculated. According to the above criteria, 12 rats in sham surgery group survived (100%), 8 rats in the model group (66%), 10 rats in experimental group (83%), and 9 rats in control group (75%) were successfully modeled. There was no statistically significant difference between the four groups (x 2=6.79, P>0.05), indicating that this method has good stability in the survival rate of rat models. Please refer to Table 2 for details.
Table 2 Effects of PF429242 on indexes of various GCIR rat groups
Groups Dosage Number Survival Neurological Pass through Average Number of (mg/kg) of rats rate of function the central speed viable cells rats Scores grid (m/s) (number of times)
Sham - 12 100% 057+0.7314 628+1.66! 054006! 109.40+8.66! surgery group
Model group - 12 66% 8.871.054 1.3340.47? 0.28+0.09? 38.60+4.632
Control 0.51 12 83% 4630.48! 5.601023 0.43+0.08° 91.606.413 group
Experimental 0.50 12 75% 4.60+1.02 5,50+1.11 0.44+0.07 84.75+3.77 group
F value oA (2) 12.449 6.569 87.359
Note: P<0.05 indicates a statistically significant difference; *P<0.05; x 2=6.79, P>0.05; ®P>0.05; compared with sham surgery group, 'P<0.05; compared with model group, 2P<0.05; compared with control group, *P>0.05; compared with sham surgery group, the model group had a P<0.05.
[0036] 5. Detection of autonomous behavior, exploratory behavior, and anxiety behavior 6
BL-5757 in rats through open-Field test LUS05115
[0037] The experiment was conducted in a quiet environment, animals were placed in the center of the bottom surface of a box, and camera shooting and timing (3 min) were simultaneously performed. The inner wall and bottom of the square box was wiped with a cloth dampened with acetic acid diluent to avoid that any residual information from the previous animal (such as feces, urine and odor of animals) affects the results of the next test. The animals were replaced to continue the experiment. Observation indicators: according to the parameters designed and observed by computer software, (1) the number and distance of animals crossing the central grid per unit time; (2) the number of urinations and stools; (3) the total distance of movement.
[0038] Analysis of the results of crossing the central grid: there was a statistically significant difference among the four groups (F=12.44, P<0.05); the rats in model group showed a significant decrease in their awareness of autonomous exploration of the surrounding environment, and the difference was statistically significant compared to sham surgery group (P<0.05), indicating that the model was successfully established; compared with experimental group, there was statistically significant difference (P<0.05), indicating that PF429242 can improve the autonomous exploration behavior and anxiety level of the rat; there was no statistically significant difference between control group and experimental group (P>0.05). Analysis of the average speed of walking in the central grid: there was statistically significant difference between the four groups (F=6.56, P<0.05); there was statistically significant difference between model group and sham surgery group (P<0.05); there was no statistically significant difference between model group and experimental group (P<0.05); there was no statistically significant difference between control group and experimental group (P>0.05). It indicates that the treatment of experimental group and control group can improve the autonomous exploration and motor ability of rats, as shown in Table 2.
[0039] 6. The effect of PF429242 on cerebral blood flow in I/R rats
[0040] After anesthesia, the skin was cut along the middle of the ears and between the eyes, and the fascia was tore. The distribution of cerebral blood flow in the prefrontal lobe of the rat for 20s was recorded by using a laser speckle flow imaging system. Result analysis: the cerebral blood flow signal of the model group was significantly lower than that of sham operation group, with a statistically significant difference (P<0.05), indicating successful modeling. Compared with model group, the cerebral blood flow in control group and administration group was significantly recovered, with a statistically significant 7
BL-5757 difference (P<0.05). PF429242 can promote the recovery of cerebral blood flow in cerebral | LU505115 ischemia rats. Sham surgery group, model group, control group and experimental group are shown in FIG. 1A, FIG. 1B, FIG. 1C, and FIG. 1D, respectively.
[0041] 7. Pathological and morphological evaluation of rat hippocampus tissue-Nissl staining
[0042] Nissl body: it is an alkaline substance in the cytoplasm and is widely found in various neurons. Under physiological conditions, the Nissl body is large and numerous, reflecting the strong function of nerve cells in synthesizing proteins. When neurons are damaged, the number of Nissl bodies can decrease or even disappear. After taking the brain, the brain was fixed with a 4% paraformaldehyde solution, dehydrated with a 30% sucrose solution, embedded in OCT and made into frozen sections with a thickness of 10 um, and then the sections were subjected to Nissl staining.
[0043] During the entire surgical process, the body temperature of the rat was maintained at around 37°C. After the surgery, the room was kept sterile, with suitable temperature and humidity, and the diet, mental state, and activity status of the rats were recorded in detail.
In sham surgery group, bilateral common carotid arteries were dissociated but blood flow was not blocked. Analysis of Nissl staining results in the CA1 area of the hippocampus of four groups of rats after 5 days of survival: there was a statistically significant difference in the number of surviving cells among the four groups (F=87.35, P<0.05); the number of neurons in ischemic model group significantly decreased compared to sham operated group, with a statistically significant difference (P<0.05); compared with experimental group, there was a statistically significant difference (P<0.05), indicating that pretreatment with PF429242 had a significant protective effect on nerve cell damage in rats; there was no statistically significant difference between experimental group and control group (P>0.05), indicating that the two drug treatments had similar protective effects on rat neurons. The above results showed that PF429242 had a significant protective effect on neural cells after global cerebral ischemia-reperfusion injury in rats.
[0044] The structure of neurons in the CAl area of the hippocampus in sham surgery group is complete, with clear layers, no obvious nuclear pyknosis, and neurons are blue stained; the arrangement of nerve cells in the experimental group and control group showed slight dispersion, and nuclear pyknosis did not appear significantly. The number of cells decreased compared to the blank group (P<0.05); the ischemia-reperfusion model group showed shallow staining of neuronal cells, disordered arrangement of neural cells, significant nuclear pyknosis, and decreased cell count. Sham surgery group, control group, 8
BL-5757 model group and experimental group are shown in FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D, LU505115 respectively.
[0045] The inventor also applied the enantiomer, racemate, and hydrochloride of
PF429242 to a rat model of global cerebral ischemia-reperfusion according to the aforementioned experimental process. The experimental results were basically consistent with those of PF429242 experimental group.
[0046] Although the present disclosure has been described with reference to illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and/or additions can be made without departing from the spirit and scope of the present disclosure, and substantial equivalents can be used to replace the components of the embodiments. In addition, many modifications can be made without departing from the scope of the present disclosure to adapt specific situations or materials to the teachings of the present disclosure. Therefore, it is not intended herein to allow the present disclosure to include all embodiments within the scope of the appended claims rather than limiting the present disclosure to the specific embodiments disclosed for executing the present disclosure. 9
Claims (6)
1. Use of PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof in preparation of a drug for preventing and/or treating cerebral ischemia-reperfusion injury.
2. The use according to claim 1, wherein the preventing and/or treating cerebral ischemia-reperfusion injury is inhibition or alleviation of the occurrence and/or progress of cerebral ischemia-reperfusion injury and/or reversion of pathologic change.
3. The use according to claim 1, wherein the drug is a composition comprising PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier or excipient.
4. Use of PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof in screening a drug for preventing and/or treating cerebral ischemia-reperfusion injury.
5. The use according to claim 4, wherein the preventing and/or treating cerebral ischemia-reperfusion injury is inhibition or alleviation of the occurrence and/or progress of cerebral ischemia-reperfusion injury and/or reversion of pathologic change.
6. The use according to claim 4, wherein the drug is a composition comprising PFPF429242, as well as enantiomers and racemates or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier or excipient.
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