CN107412214A - A kind of application of phosphodiesterase 4 inhibitors - Google Patents
A kind of application of phosphodiesterase 4 inhibitors Download PDFInfo
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
The invention discloses a kind of application of phosphodiesterase 4 inhibitors, described phosphodiesterase 4 inhibitors are FCPR16, and its structural formula is：；Described FCPR16 is applied to prevent or treated in the medicine of Parkinson's, or applied in medicine of the preparation for repairing dopaminergic neuron damage.Its purposes in treatment PD medicines are prepared belongs to first public, new application field is expanded for PDE4D inhibitor FCPR16, and its dyskinesia to PD has good effect；It can repair the retrogression of dopaminergic neuron or Apoptosis or oxidative damage.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of application of phosphodiesterase 4 inhibitors.
Background technology
Parkinson's (Parkinson's disease, PD) are a kind of central nervous system degenerative diseases, are mostly occurred
Yu Zhong, elderly population, with the aggravation of social population ageing phenomenon, PD gives the quality of life of patient itself and family band
Carry out serious influence.The disease major pathologic features are that nigral dopaminergic neuron progressive is lost, and further result in corpus straitum
Interior DOPAMINE CONTENT IN RABBIT is reduced.The precise mechanism for causing this disease is not yet clear and definite, and existing research generally believes and environmental factor, line
Mitochondria function obstacle, inherent cause, oxidative stress, gene mutation, neurotoxicity, inflammation and autophagy etc. are relevant, it is also possible to
By the coefficient result of many factors.PD main clinical manifestation be myotonia, progressive bradykinesia, static tremor with
And posture gait disorder etc..The disease not yet finds effective medicine and method at present, and existing treatment means are main
Based on drug therapy, it is aided with lesions located in deep brain cell transplantation and gene therapy etc..PD sings and symptoms can be carried
The medicine of high Dopamine is alleviated, and wherein representative drugs are levodopas, but a series of secondary works that levodopa occurs
With limiting its extensive use.More disappointed to be, if long-term use of, levodopa may damage neuron, accelerate
The apoptosis of neuron.So exploring the mechanism of PD occurrence and development and finding optimal PD therapeutic strategies has very great meaning
Justice.
Phosphodiesterase (Phosphodiesterase, PDEs) is catalyzing hydrolysis extremely important second messenger into the cell
CAMP and cGMP enzyme super families, played adjusting internal cAMP and cGMP level, the process for participating in a variety of diseases etc.
Most important effect.PDE4 is specific catalytic hydrolysis cAMP enzyme.In recent years, preclinical laboratory research shows suppression maincenter
Nervous system PDE4 has significant neuroprotection.But traditional PDE4 inhibitor such as Rolipram can produce it is serious not
Good reaction, wherein Nausea and vomiting are the most prominent, patient's poor compliance, cause it to cannot be introduced into Clinical practice.Thus it is guaranteed that medicine
It is the bottleneck for developing PDE4 inhibitor class antidepressants that thing is effective, reduces adverse drug reaction.
FCPR16 is a new PDE4 inhibitor, compared with traditional PDE4 inhibitor such as Rolipram, FCPR16 suppressions
PDE4 processed IC50Value is significantly lower than control compound Rolipram, i.e. its enzyme inhibition activity to PDE4 compared with Rolipram more
By force.Meanwhile FCPR16 has gone out higher selectivity to PDE4D7 this subtype displays, i.e., to the selectivity of PDE4D hypotypes compared with
It is high.Most obvious advantage is that there is FCPR16 very low cause to cause vomiting potential, shows fabulous clinical value.Existing skill
The compound is disclosed in art, referring to Development of highly potent phosphodiesterase
4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and
structure-activity relationship study of catecholamides bearing aromatic
rings. Eur J Med Chem. 2016;124:372-379. does not still disclose its use on treatment of Parkinson disease
On the way.
The content of the invention
The technical problem to be solved by the invention for the present situation of prior art is to provide Novel PDE 4 inhibitors FCPR16
Application on antiparkinsonism drug, its dyskinesia to PD have good effect；Additionally provide Novel PDE 4 suppression
Applications of the agent FCPR16 in dopaminergic neuron damage is repaired.
Technical scheme is used by the present invention solves above-mentioned technical problem：
A kind of application of phosphodiesterase 4 inhibitors, phosphodiesterase 4 inhibitors FCPR16, its structural formula are：
；
FCPR16 is applied to prevent or treated in the medicine of Parkinson's, or is used to repair dopaminergic nerve applied to preparing
In the medicine of member damage.
To optimize above-mentioned technical proposal, the concrete measure taken also includes：
Above-mentioned FCPR16, which is applied to prepare, to be used to repair caused by the Parkinson's in the medicine of trauma of cerebral nerve cell.
FCPR16 compounds or its drug acceptable salt are included in above-mentioned medicine.
The administering mode of above-mentioned medicine is ejection preparation, oral formulations or external preparation.
The dosage form of above-mentioned medicine includes tablet, capsule, powder, pill, granule, injection or emulsion.
Compared with prior art, PDE4D inhibitor FCPR16 of the invention is applied in antiparkinsonism drug, and it is being made
Purposes in standby treatment PD medicines belongs to first public, and its dyskinesia to PD has good effect；Additionally provide
Applications of the Novel PDE 4 inhibitors FCPR16 in dopaminergic neuron damage is repaired, it can repair dopaminergic neuron
Retrogression or Apoptosis or oxidative damage.
Brief description of the drawings
Fig. 1 is the Parkinson disease mice that FCPR16 is induced MPTP in suspension experiment (A) and Grasping clubglass test (B)
The influence of motor function；
Fig. 2 is influences of the FCPR16 to the MPTP Parkinson disease mice motor functions induced in turn-club test；
Fig. 3 is the influence for the Parkinson disease mice autonomic activities that FCPR16 is induced MPTP；
Fig. 4 is influences of the FCPR16 to PD transgenic mice motor functions in suspension experiment (A) and Grasping clubglass test (B)；
Fig. 5 is influences of the FCPR16 in turn-club test to PD transgenic mice motor functions；
Fig. 6 is Flow cytometry FCPR16 to MPP+The influence of SH-SY5Y Apoptosis after modeling；
Fig. 7 is FCPR16 to MPP+To the influence of SH-SY5Y intracellular ROS levels after modeling.
Embodiment
The present invention is described in further detail below in conjunction with accompanying drawing embodiment.
A kind of application of phosphodiesterase 4 inhibitors, phosphodiesterase 4 inhibitors FCPR16, its structural formula are：
；
FCPR16 is applied to prevent or treated in the medicine of Parkinson's.Or it is used to repair dopaminergic nerve applied to preparing
In the medicine of member damage；Prepared medicine is used for retrogression or Apoptosis or the oxygen that can repair dopaminergic neuron
Change damage.
In embodiment, FCPR16 compounds or its drug acceptable salt are included in medicine.
In embodiment, the administering mode of medicine is ejection preparation, oral formulations or external preparation.
In embodiment, the dosage form of medicine includes tablet, capsule, powder, pill, granule, injection or emulsion.
PDE4D inhibitor FCPR16 anti-parkinson is confirmed below by experiment and repairs dopaminergic neuron damage
Effect in wound.
Test the PD model mices fortune that 1. FCPR16 are induced MPTP (MPTP)
The improvement result of dynamic function
Experimental animal and administration processing：The male C57BL/6 mouse of 72 10 week old are chosen, adapt to environment two weeks, body weight is
(20-25) g, it is dark to receive 12 h illumination/12 h daily.20 ± 2 DEG C of laboratory temperature, humidity 60%, animal can voluntarily be taken the photograph
Take standard feed and cleaning water.Experimental animal is in accordance with International Laboratory Animal ethics requirement.Mouse is randomly divided into 6 groups, often
Group 12, blank control (control) group, MPTP groups, low dose group (1.25 mg/kg FCPR16+MPTP), middle dose group
(2.5 mg/kg FCPR16+MPTP), high dose group (5.0 mg/kg FCPR16+MPTP), positive drug control group (25.0
Mg/kg levodopas+MPTP), weigh and record body weight.First day of experiment, low dose group, middle dose group, high dose group
Mouse distinguishes the mg/ml of gavage 0.125,0.25 mg/ml, 0.5 mg/ml FCPR16 solution by the ml/kg of body weight 10 volume,
Make the FCPR16 that medicine activity is 1.25 mg/kg, 2.5 mg/kg and 5.0 mg/kg.The solvent of above solution is all
0.5% CMC-Na solution, second day to the 6th day of experiment, low dose group, middle dose group and high dose group were first filled with FCPR16
Stomach, 0.5% CMC-Na solution of remaining group gavage isometric(al).MPTP groups, low dose group, middle dose group, high dose group after 1 h
It is injected intraperitoneally 30 mg/kg MPTP with positive controls, the physiological saline of the capacity such as blank group intraperitoneal injection, continuous 5 days.It is real
Test the 7th day to the 15th day, positive controls mouse presses the ml/kg of body weight 10 mg/kg of volume gavage 2.5 levodopa
Solution, solvent are 0.5% CMC-Na solution.The 16th day, i.e. MPTP final injections the tenth day are tested, takes each group mouse to enter every trade
Tested to learn.
Autonomic activities tests (open field)：Make the cm of the cm of 30 cm × 30 × 15 tub by oneself, bottom carve 6 cm ×
6 cm grid, detected in quiet, dark environment.After mouse adapts to the min of environment 10, count mouse in 5 min and move
The grid number of dynamic (ambulation) and the number of standing (rearing).
Roller bearing tests (rotarod)：Roller bearing experiment needs animal to keep balancing and continuously moving on roller bearing, is to adopt extensively
Detect the experiment of sports coordination.Before experiment, every mouse trains 5 min, can be in big mouse fatigue transfer rod instrument
Upper stop, 5 min that then rest start to test, and rotating speed is 12 rpm.The time is terminated using 180 seconds as experiment.Record mouse exists
Residence time in tired transfer rod instrument.
Grasping clubglass test (pole test)：Make the cm of diameter 0.8, high 60 cm straight rod by oneself, a small wooden shot is arranged at bar top,
Outside covers gauze to prevent mouse from skidding.Mouse is placed in top dome, records following 3 times：Mouse bead at the top of rod stops
The time stayed；The time required to mouse has climbed the top half of bar length；Mouse has climbed the time needed for the latter half of bar length；By with
Lower scale：The note 3 for completing any action in 3 seconds is divided, and 2 points are remembered in 6 seconds, and 1 point was remembered more than 6 seconds, is finally calculated three and is added up
Scoring event.
Suspension experiment (grid test)：The horizontal positioned mm of metal shank diameter 1.5 is made by oneself, away from the cm of ground 30, in experiment
The double forelimbs of mouse are hung in a horizontal wire, as mouse with double hind legs catches 3 points of electric wire note；Only electricity is caught with a hind leg
Line remembers 2 points；Two hind legs fail to grip with 1 point of note；Mouse, which falls, is designated as 0 point.
Experimental result：By establishing stable Asia using intraperitoneal injection MPTP (30 mg/kg) method in C57BL mouse
Acute Parkinson disease model, investigate whether FCPR16 has the function that to anti-parkinson dyskinesia on the basis of this model.
In Grasping clubglass test we can observe that：Blank control group mouse freedom of movement, completion required movement is less with the used time, obtains
Higher fractional.MPTP causes model group mouse movement slow, and completion required movement is longer with the used time, obtains relatively low fraction, and
It is substantially higher (P than MPTP group mouse that FCPR16 drug-treateds group obtains fraction<0.05).In suspension is tested, blank control group group
Mouse can catch electric wire with four limbs；And MPTP groups mouse can only catch electric wire with fore paw, rear solid end is powerless, and score is relatively low；
FCPR16 treatment group mouse rear solid end strength is remarkably reinforced, and at least can catch electric wire with a rear solid end.As a result such as part A in Fig. 1
In (suspension experiment) and Fig. 1 shown in part B (Grasping clubglass test).
Further FCPR16 is evaluated to Parkinson using being used to evaluate the classical animal model turn-club test of anti-PD medicines
The improvement result of sick dyskinesia.Mouse is trained early stage, and screening obtains the qualified mouse of motor function, will after success modeling
Mouse is placed in the transfer rod instrument of operating, starts timing.Record mouse on transfer rod residence time as incubation period (i.e. the
The time once dropped) its sports coordination ability represented with this.Every mouse assay 3 times, per minor tick 30min, average.
As a result Fig. 2 is seen, it has been found that Normal group mouse does not almost drop in 2 min, and incubation period is designated as 120 seconds.MPTP moulds
The sports coordination ability of type group mouse is decreased obviously, and is had significant difference compared with Normal group mouse, is shown as hiding
Phase substantially shortens, and the number that drops dramatically increases (P<0.01).And observe the accumulation damaged with MPTP, the dyskinesia of mouse
Aggravated in progressive.Compared with MPTP model groups, FCPR16 and positive control drug levodopa (L-dopa) organize mouse in transfer rod
The incubation period of upper stop is obviously prolonged (P<0.05).
After obtaining FCPR16 and can significantly improve the dyskinesia of PD model mices, we further have rated this
Influence of the compound to mouse autonomic activities, whether there is central excitation or central inhibitory action with the clearly compound.As a result
See Fig. 3, it has been found that FCPR16 does not influence in the unit interval mouse in the center lattice residence time, the grid number that a certain limbs are crossed
For horizontal score (crossing), hind leg standing number is that vertical score (rearing) no conspicuousness compared with model group is poor
Different, i.e. FCPR16 does not influence the autonomic activities of mouse in the PD models that MPTP is induced.
Test improvement results of 2. FCPR16 to PD transgenic mice dyskinesia
Experimental animal and administration processing：PD transgenic animals are synuclein transgenic mices, and PD trangenic mices and WT mouse are daily
It is dark to receive 12 h illumination/12 h.20 ± 2 DEG C of laboratory temperature, humidity 60%, animal can voluntarily absorb standard feed and clear
It is clean to use water.Experimental animal is in accordance with International Laboratory Animal ethics requirement.When PD trangenic mices and WT 16 week old of mouse, it is carried out
Behaviors survey.
The Behaviors survey of PD model mice dyskinesia is detected with experiment 1.
Experimental result：The dyskinesia of mouse can be improved by obtaining FCPR16 in the PD model mices of MPTP inductions
Afterwards, we further investigate FCPR16 effect using PD α-Synuclein transgenic mices.As a result it is as shown in figure 4, continuous
Gavage gives FCPR16 after totally 21 days, is hung and Grasping clubglass test, the locomitivity of α-Synuclein transgenic mices are notable
It is impaired, and after giving FCPR16, then the locomitivity of mouse is significantly improved, compared with transgenic mice, there is significant difference
(P<0.05)。
We equally employ classical turn-club test to evaluate FCPR16 to changing to PD transgenic mice dyskinesia
Kind effect, is as a result shown in Fig. 5, consistent with the result of MPTP model mices, FCPR16 dramatically increase mouse stopped on transfer rod it is latent
Volt phase (P<0.05).
3. FCPR16 are tested to MPP+Dopaminergic nerve cell SH-SY5Y protective effect after modeling
Flow cytometry detects Apoptosis：The SH-SY5Y cells in exponential phase are taken out, are digested, are centrifuged, weight
It is outstanding.The concentration of appropriate culture medium and serum adjustment cell suspension is added, carries out the plating cells of six orifice plates, cell puts incubator mistake
After night, the FCPR16 solution of various concentrations is added, puts and adds MPP after 2 h are cultivated in incubator+Solution, make the MPP in hole+Solution
Final concentration of 500 mol/L, put after continuing to cultivate 24 h in incubator, six holes after experiment process are taken out from incubator
Plate, each hole are digested, centrifugation, careful supernatant discarding, are added the culture medium containing 1% serum, 1% bovine serum albumin(BSA) and are carried out cell
It is resuspended, takes 100 μ l cell suspensions into centrifuge tube.Cell apoptosis detection kit is taken out, often pipe adds 100 μ l Annexin
V/7-ADD coloring agents, gently piping and druming mix cell, are incubated 20 min, upper machine testing at room temperature.Result is carried out after detection
Analysis, wherein Annexin V (-), 7-AAD (-) represent non-apoptotic cell；Annexin V (+), 7-AAD (-) represent early
Phase apoptotic cell；Annexin V (+), 7-AAD (+) represent late apoptic and dead cell；Annexin V (-)、7-AAD
(+) represents fragment.
Intracellular reactive oxygen level detects：The SH-SY5Y cells in exponential phase are taken out, are digested, are centrifuged, weight
It is outstanding.The concentration of appropriate culture medium and serum adjustment cell suspension is added, carries out the plating cells of six orifice plates, cell puts incubator mistake
After night, the FCPR16 solution of various concentrations is added, puts and adds MPP after 2 h are cultivated in incubator+Solution, make the MPP in hole+Solution
Final concentration of 500 mol/L, put after continuing to cultivate 2 h in incubator, according to 1:1000 dilute DCFH- with serum-free medium
DA, make final concentration of 10 mol/L, remove nutrient solution, add the DCFH-DA that proper volume has diluted.In 37 DEG C of cell culture incubators
20 min are incubated, cell is washed three times with serum free medium, intracellular DCFH-DA is introduced into abundant removal.It is inverted glimmering
The change of viewed under light microscopy intracellular reactive oxygen level, excitation wavelength are 488 nm, and launch wavelength is 525 nm, per hole with
Machine chooses eight visuals field and carries out observation statistics.
Experimental result：Using Flow cytometry FCPR16 to MPP+Dopaminergic nerve cell SH-SY5Y after modeling
The influence of apoptosis, as a result such as Fig. 6.Compared with Normal group, MPP+Early apoptosis (25.53%) and late period are in model group
Apoptosis (7.48%) substantially increases, and gives 25 μM of FCPR16 processing cells merely, Apoptosis quantity and normal control phase
Than changing unobvious.And compared with model group, can be after giving 6.3 μM, 12.5 μM or 25 μM FCPR16 processing cells
The quantity of apoptotic cell is reduced in varying degrees.Wherein, 12.5 μM of FCPR16 processing cells, the cell number of early apoptosis are given
Amount is decreased obviously (15.12%), and late apoptic and dead cell change are little.25 μM of FCPR16 processing cells are given, are in
Early apoptosis is presented and is decreased obviously (11.18%), and late apoptic and number of dead cells are also on a declining curve.
SH-SY5Y cytoactives oxygen (ROS) is detected using dyeing, as a result such as Fig. 7.Normal group and simple
It is shallower to give 25 μM of FCPR16 treatment group cell red fluorescences, shows that now cell ROS levels are relatively low, and MPP+Modeling group is thin
Born of the same parents are in mainly stronger red fluorescence, show that now cell ROS levels are higher, MPP+There is oxidative damage to SH-SY5Y cells
Toxicity.And 25 μM of FCPR16 treatment group cells are through MPP+After modeling, red fluorescence weakens, and illustrates that FCPR16 can weaken
MPP+Increase horizontal ROS in SH-SY5Y cells after modeling, weakens MPP+To the damaging action of SH-SY5Y cells.
Highly preferred embodiment of the present invention has been elucidated with, the various change made by those skilled in the art or remodeling all without
Depart from the scope of the present invention.
Claims (4)
1. a kind of application of phosphodiesterase 4 inhibitors, it is characterized in that：Described phosphodiesterase 4 inhibitors are FCPR16, its
Structural formula is：
；
Described FCPR16 is applied to prevent or treated in the medicine of Parkinson's, or is used to repair dopamine applied to preparing
In the medicine of serotonergic neuron damage.
2. a kind of application of phosphodiesterase 4 inhibitors according to claim 1, it is characterized in that：Wrapped in described medicine
Compound containing FCPR16 or its drug acceptable salt.
3. a kind of application of phosphodiesterase 4 inhibitors according to claim 2, it is characterized in that：Described medicine is given
Prescription formula is ejection preparation, oral formulations or external preparation.
4. a kind of application of phosphodiesterase 4 inhibitors according to claim 3, it is characterized in that：The system of described medicine
Dosage form formula includes tablet, capsule, powder, pill, granule, injection or emulsion.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110279686A (en) * | 2019-08-01 | 2019-09-27 | 汪海涛 | A kind of phosphodiesterase 4 inhibitors are preventing and are treating the application in Parkinson's disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523954A (en) * | 2016-02-05 | 2016-04-27 | 徐江平 | Novel 3-cyclopropylmethoxy-4-alkoxybenzamide PDE (phosphodiesterase) 4 inhibitors |
-
2017
- 2017-07-31 CN CN201710636918.9A patent/CN107412214A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523954A (en) * | 2016-02-05 | 2016-04-27 | 徐江平 | Novel 3-cyclopropylmethoxy-4-alkoxybenzamide PDE (phosphodiesterase) 4 inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| LICHUAN YANG等: "Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV", 《EXPERIMENTAL NEUROLOGY》 * |
| PHILIPPA HULLEY等: "Inhibitors of Type IV Phosphodiesterases Reduce the Toxicity of MPTP in Substantia Nigra Neurons In Vivo", 《EUROPEAN JOURNAL OF NEUROSCIENCE》 * |
| ZHONG-ZHEN ZHOU等: "Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 王越等: "连翘苷对LPS刺激的BV2小胶质细胞炎性反应的抑制作用", 《中风与神经疾病杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110279686A (en) * | 2019-08-01 | 2019-09-27 | 汪海涛 | A kind of phosphodiesterase 4 inhibitors are preventing and are treating the application in Parkinson's disease |
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