CN105663136A - Application of fasudil to preparation of Kv7 ion channel activator medicament with selectivity - Google Patents
Application of fasudil to preparation of Kv7 ion channel activator medicament with selectivity Download PDFInfo
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- CN105663136A CN105663136A CN201610027268.3A CN201610027268A CN105663136A CN 105663136 A CN105663136 A CN 105663136A CN 201610027268 A CN201610027268 A CN 201610027268A CN 105663136 A CN105663136 A CN 105663136A
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- fasudil
- acid
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- channel activator
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
Abstract
The invention relates to an application of fasudil to preparation of Kv7 ion channel activator medicament with selectivity. Fasudil can be used for one or more regulation, such as regulation of current, voltage and vascular tension of Kv7.4 and Kv7.4/7.5 potassium channels. During usage, fasudil has selective activation effects for Kv7.4/7.5 ion channels, and can be used for preparation of medicaments for reducing blood pressure.
Description
Technical field
The present invention relates to the application of fasudil in pharmacy, the specifically application of 5-isoquinoline 99.9 sulfonamides compound fasudil in pharmacy, especially as the application of preparation selectivity Kv7 ionic channel activator medicine.
Background technology
5-isoquinoline 99.9 sulfonamides compound fasudil (fasudil); Chinese chemical name: six hydrogen 1 (5 alkylsulfonyl isoquinoline 99.9) 1 (H) 1; 4 diazepines; English language Chemical title: 5-(1,4-Diazepane-1-sulfonyl) isoquinoline. Molecular formula is C14H17N3O2S, relative molecular mass is 291.36, white or off-white powder, and this product is very easily molten in water, dissolves in methyl alcohol, slightly molten in ethanol, atomic molten in chloroform, almost insoluble in ether, No. CAS: 103745-39-7.
Valtage-gated Kv7 potassium channel family is an important branch of valtage-gated potassium channel superfamily, being played an important role in control myocardial action potential, neuronal excitability and smooth muscle tension aspect, its chemistry small-molecule modulators is an important selection of current new drug development. Kv7 potassium channel family is by KCNQ genes encoding, there are six membrane spaning domains (S1-S6), 1-4 membrane spaning domain (S1-S4) forms the voltage susceptor of passage, and S5-S6 and the connection portion (S5-P-S6) between the two form the hole district of passage. Up to now, find five member: Kv7.1-Kv7.5 of this family altogether.
The Rho kinase inhibitor that fasudil is, by increasing the active vasodilation of Myosin light chain phosphatase, reduces the tension force of endotheliocyte; improve cerebral tissue microcirculation, do not produce and increase the weight of robber's blood of brain, simultaneously can the anti-inflammatory factor short of money; patron saint, through anti-apoptotic, promotes neurotization. Being mainly used in preventing and improve the vasospasm that multiple reason causes, the blood vessel of selectivity expansion spasm, improves the heart, cerebral ischemia ability, improves brain perfusion, strengthens the aspects such as brain anti-anoxia ability. But do not find so far not retrieve the report being used to the medicine containing fasudil for the treatment of with Kv7 potassium-channel related diseases, such as hypertension aspect and pertinent literature yet.
Summary of the invention
It is an object of the invention to provide a kind of medicine being used as preparation selectivity Kv7.4, Kv7.4/7.5 potassium-channel activator.
The object of the present invention is achieved like this:
The present invention provides the novelty teabag of a kind of 5-isoquinoline 99.9 sulfonamides compound fasudil, as the application of preparation selectivity Kv7 ionic channel activator, namely with 5-isoquinoline 99.9 sulfonamides compound fasudil as Kv7.4, Kv7.4/7.5 ionic channel activator, Kv7.4/7.5 refers to Kv7.4 and Kv7.5 ionic channel mosaic.
Kv7.4, Kv7.4/7.5 ionic channel described above activates and refers to: fasudil is to one or more in the adjustment of Kv7.4, Kv7.4/7.5 potassium-channel electric current, the adjustment of voltage, the adjustment of antiotasis.
Fasudil is as the application of preparation selectivity Kv7 ionic channel activator, and described fasudil can adopt the form of free alkali or salt to exist; When fasudil adopts the form of salt to apply, the mineral acid (example hydrochloric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid) allowed on physiology, organic acid (such as acetic acid, propionic acid, citric acid, toxilic acid, oxysuccinic acid, tartrate, methylsulfonic acid) can be selected to become salt.
In use Kv7.4/7.5 ionic channel there is is selectivity agonism, can be used as the medicine that preparation reduces blood pressure.
Compound of the present invention all can obtain from commercial channel.
5-isoquinoline 99.9 sulfonamides compound fasudil provided by the invention, as the medicine of preparation Kv7.4, Kv7.4/7.5 ionic channel activator, with the carrier pharmaceutically allowing to use or mixing diluents, is prepared into pharmaceutical preparation.
The present invention is referred to the carrier that pharmaceutically can accept or thinner, vehicle, auxiliary material or the solvent that can be selected from pharmaceutical preparation conventional. Such as the lower alkyl ether of lactose, sucrose, dextrin, talcum powder, gelatin, agar, pectin, Sudan Gum-arabic, Magnesium Stearate, stearic acid, Mierocrystalline cellulose, W-Gum, yam starch, natural gum, syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, single stearic acid glycerine lipoprotein or glycerol disterate fat, tinting material, correctives, sanitas, water, ethanol, propyl alcohol, physiological saline, glucose solution etc.
Concrete preparation method using 5-isoquinoline 99.9 sulfonamides compound fasudil as Kv7.4, Kv7.4/7.5 ionic channel activator provided by the invention can carry out according to preparation routine. As can compound of the present invention as active ingredient, be prepared into oral liquid with water, sucrose, sorbyl alcohol sugar, fructose etc.; Can also lactose, glucose, sucrose, N.F,USP MANNITOL sugar etc. being vehicle, taking starch etc. as disintegrating agent, taking stearic acid, talcum powder etc. as lubricant, gelatin, polyvinyl alcohol be that bonding agent is prepared into tablet or capsule; Also can be prepared into injection liquid with the mixed carrier of physiological saline, glucose solution or salt solution and glucose composition. Also can be made into sterile powder injection and various sustained release dosage, suspensoid, emulsion etc.
5-isoquinoline 99.9 sulfonamides compound fasudil provided by the present invention can be used for the hypertension owing to Kv7.4, Kv7.4/7.5 ion channel function obstacle or other reasons cause as Kv7.4, Kv7.4/7.5 ionic channel activator.
Accompanying drawing explanation
Fig. 1 fasudil is to the regulating effect of Kv7 potassium-channel family.
A fasudil is to the regulating effect of Kv7 potassium-channel family (Kv7.1-7.5) electric current.
B fasudil increases the schematic diagram of Kv7.4 potassium-channel electric current.
C fasudil increases the tune schematic diagram of Kv7.4/7.5 potassium-channel electric current.
D fasudil is to the statistics of the regulating effect of Kv7 potassium-channel family (Kv7.1-7.5) electric current.
Fig. 2 fasudil is to the dose-effect relationship of Kv7 potassium-channel family regulating effect.
A fasudil increases the dose-effect relationship of Kv7.4 potassium-channel.
B fasudil increases the dose-effect relationship of Kv7.4/7.5 potassium-channel.
C fasudil is to the schematic diagram of Kv7.2/7.3 potassium-channel galvanic action.
D fasudil is to the dose-effect relationship of Kv7.2/7.3 potassium-channel effect.
Fig. 3 fasudil is to the regulating effect of the conductance-voltage curve of Kv7 potassium-channel family.
A fasudil is to the regulating effect of the conductance-voltage curve of Kv7.4 potassium-channel.
B fasudil is to the regulating effect of the conductance-voltage curve of Kv7.4/7.5 potassium-channel.
C fasudil is to the regulating effect of the conductance-voltage curve of Kv7.2 potassium-channel.
D fasudil is to the regulating effect of the conductance-voltage curve of Kv7.2/7.3 potassium-channel.
Fig. 4 fasudil is to the regulating effect of Dorsal root ganglion M/Kv7 potassium current and membrane potential.
A fasudil is to the schematic diagram of the regulating effect of Dorsal root ganglion M/Kv7 potassium current.
B fasudil is to the statistical graph of the regulating effect of Dorsal root ganglion M/Kv7 potassium current.
C fasudil is to the schematic diagram of the regulating effect of Dorsal root ganglion membrane potential.
D fasudil is to the statistical graph of the regulating effect of Dorsal root ganglion membrane potential.
Fig. 5 fasudil is to the regulating effect of rat mesentery two grades of arteries tension force.
A fasudil diastole rat mesentery two grades of arterial vascular schematic diagram.
After B hatches Kv7 potassium channel blocker XE991 in advance, fasudil diastole rat mesentery two grades of arterial vascular schematic diagram.
C fasudil diastole rat mesentery two grades of arterial vascular dose-effect relationships.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, but the present invention is not limited to following examples.
Following examples fasudil used is Fasudil Hydrochloride.
Embodiment 1 electro physiology patch clamp measures fasudil (fasudil) to the increase effect of Kv7.4, Kv7.4/7.5 potassium channel current.
(1) test compounds fasudil: commercial fasudilCAS:103745-39-7 (Sigma article No.: CDS021620);
(2) testing method: the cultivation of human embryonic kidney cell (HEK293A): adopt and Lipofectamine2000reagent (Invitrogen) wink turned rat Kv7.1/KCNE1, Kv7.2, Kv7.2/7.3, Kv7.4, the HEK293A cell cultures of Kv7.4/7.5 passage is in containing 10% foetal calf serum, in the DMEM nutrient solution of 100U/ml penicillin and Streptomycin sulphate, trysinization is gone down to posterity. Being laid on by cell on the circular lid slide of 12mm, 24 orifice plates are cultivated;
Patch clamp technique record membrane currents: patch clamp amplifier adopts Axon700B. In electrode, punching Patch-clamp techniques is done in application amphotericin B (final concentration 0.1～0.2mg/ml). After microelectrode polishing, liquid in filling electrode, controlling resistance value is at 1.5～2.5M Ω. In record electrode used therein, liquid is (mM): KCl150, HEPES10, MgCl25, adjust pH to 7.4 with KOH; Extracellular fluid component is (mM): NaCl160, KCl2.5, HEPES10, glucose8, MgCl21, CaCl25, extracellular fluid also adds fasudil (such as 30 micromoles per liter etc.) simultaneously, after microelectrode and cytolemma form huge resistance sealing-in, clamp down on and start to carry out electric current record according to different stimulation programs after-80mV waits 5-10min.
(3) test result: as can be seen from Figure 1,30 micromoles per liter fasudil can increase Kv7.4, Kv7.4/7.5 channel current amplitude. And do not affect Kv7.2, Kv7.2/7.3 channel current amplitude, slight suppression Kv7.1/KCNE1 channel current amplitude. 30 micromoles per liter fasudil can make Kv7.4, Kv7.4/7.5 channel current amplitude increase 1.26 ± 0.14 times and 1.54 ± 0.23 times (referring to Fig. 1 D).
Embodiment 2 electro physiology patch clamp measures fasudil (fasudil) and regulates Kv7.4, the dose-effect relationship of Kv7.4/7.5, Kv7.2/7.3 potassium channel current.
(1) test compounds: fasudil;
(2) testing method: with embodiment 1 method therefor.
(3) test result: as shown in Figure 2, fasudil can increase Kv7.4, Kv7.4/7.5 channel current amplitude, half maximum effective concentration (ED by concentration dependent50) it is respectively: 12.8 ± 4.4 micromoles (Kv7.4), 13.5 ± 1.7 micromoles (Kv7.4/7.5).
Embodiment 3 electro physiology patch clamp measures fasudil (fasudil) and regulates Kv7.4, the conductance-voltage curve of Kv7.4/7.5, Kv7.2, Kv7.2/7.3 potassium channel.
(1) test compounds: fasudil;
(2) testing method: with embodiment 1 method therefor.
(3) test result: as shown in Figure 3,30 micromoles per liter fasudil can make Kv7.4, Kv7.4/7.5 passage conductance-voltage curve significantly moves to left (referring to Fig. 3 A, B), and not affecting Kv7.2, Kv7.2/7.3 passage conductance-voltage curve (refers to Fig. 3 C, D).
Embodiment 4 electro physiology patch clamp measures fasudil (fasudil) to the regulating effect of Dorsal root ganglion M/Kv7 (mainly for Kv7.2 and Kv7.3) potassium current and membrane potential.
(1) test compounds: fasudil;
(2) testing method: the cultivation in SD Dorsal root ganglion in 1 week age (DRG): get the whole dorsal root ganglion of SD rat in 1 week age, collagenase, trysinization, containing 10% foetal calf serum, the DMEM nutrient solution of 100U/ml penicillin and Streptomycin sulphate blow loose, born of the same parents are laid on the circular lid slide of 12mm, and 24 orifice plates are cultivated.
Patch clamp methods is with embodiment 1 method therefor.
(3) test result: as shown in Figure 3, Dorsal root ganglion M/Kv7 potassium current (referring to Fig. 4 A, 4B) and membrane potential (referring to Fig. 4 C, D) are not made significant difference by 1～30 micromoles per liter fasudil. Dorsal root ganglion M/Kv7 potassium current is had weak restraining effect (referring to Fig. 4 A, B) by 100 micromoles per liter fasudil.
Embodiment 5 capillary blood vessel tension detection fasudil (fasudil) is to the regulating effect (being Kv7.4 and Kv7.5 on blood vessel) of rat mesentery two grades of arteries tension force.
(1) test compounds: fasudil
(2) testing method: the mensuration of adult SD rats (200～250g) mesentery two grades of arteries tension force: get adult SD rats mesentery two grades of arteries. The mensuration of antiotasis adopts DMT (ADInstruments, UK). Blood vessel preshrinking adopts 10 micromole's phyenlephriniums (Phe). The record of antiotasis adopts PowerLabandChart (version5, ADInstruments, UK).
(3) test result: as shown in Figure 5, fasudil can concentration dependent diastole rat mesentery two grades of arteries, half maximum inhibition concentration (IC50) it is 0.83 ± 0.25 micromole (referring to Fig. 5 A, C). After hatching Kv7 potassium channel blocker XE991 in advance, amount effect curve significantly moves to right, IC50It is 5.04 ± 0.96 micromoles (referring to Fig. 5 B, C).
Embodiment 6 prepares oral tablet
Preparing tablet according to methods known in the art, every sheet contains following compositions:
Claims (8)
1. fasudil is as the application of preparation selectivity Kv7 ionic channel activator medicine.
2. fasudil is as the application of preparation Kv7.4, Kv7.4/7.5 ionic channel activator medicine.
3. fasudil is as the application of preparation Kv7.4, Kv7.4/7.5 ionic channel activator medicine, it is characterized in that, Kv7.4, Kv7.4/7.5 ionic channel activates and refers to: fasudil is to one or more in the adjustment of Kv7.4, Kv7.4/7.5 potassium-channel electric current, the adjustment of voltage, the adjustment of antiotasis.
4. fasudil is as the application of preparation Kv7.4, Kv7.4/7.5 ionic channel activator medicine, it is characterised in that, described fasudil adopts the form of free alkali or salt to exist.
5. according to fasudil according to claim 4 as the application preparing Kv7.4, Kv7.4/7.5 ionic channel activator medicine, it is characterised in that, when fasudil adopts the form of salt to apply, select the mineral acid allowed on physiology, organic acid to become salt.
6. according to fasudil according to claim 5 as the application preparing Kv7.4, Kv7.4/7.5 ionic channel activator medicine, it is characterised in that, mineral acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid; Organic acid is selected from acetic acid, propionic acid, citric acid, toxilic acid, oxysuccinic acid, tartrate, methylsulfonic acid.
7. fasudil is as the application of preparation Kv7.4, Kv7.4/7.5 ionic channel activator medicine, it is characterised in that, for the preparation of the medicine reducing blood pressure.
8. fasudil is as the application of preparation Kv7.4, Kv7.4/7.5 ionic channel activator medicine, it is characterised in that, it may also be useful to the carrier pharmaceutically allowed or mixing diluents, be prepared into pharmaceutical preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019161877A1 (en) * | 2018-02-20 | 2019-08-29 | H. Lundbeck A/S | Alcohol derivatives as kv7 potassium channel openers |
| US10590067B2 (en) | 2018-02-20 | 2020-03-17 | H. Lundbeck A/S | Alcohol derivatives of carboxamides as Kv7 potassium channel openers |
| US11548849B2 (en) | 2019-08-02 | 2023-01-10 | H. Lundbeck A/S | Alcohol derivatives as KV7 potassium channel openers |
Citations (1)
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| CN1729984A (en) * | 2005-08-01 | 2006-02-08 | 吴良信 | Freeze dry formulation of fasudil hydrochloride and its preparation process |
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2016
- 2016-01-15 CN CN201610027268.3A patent/CN105663136A/en active Pending
Patent Citations (1)
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| CN1729984A (en) * | 2005-08-01 | 2006-02-08 | 吴良信 | Freeze dry formulation of fasudil hydrochloride and its preparation process |
Non-Patent Citations (2)
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| 关胜江等: "Rho激酶抑制剂对异丙肾上腺素诱导大鼠心肌肥厚的影响", 《中国老年学杂志》 * |
| 张园园: "Rho激酶抑制剂Fasudil对Kv7钾通道选择性调节作用的研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019161877A1 (en) * | 2018-02-20 | 2019-08-29 | H. Lundbeck A/S | Alcohol derivatives as kv7 potassium channel openers |
| US10590067B2 (en) | 2018-02-20 | 2020-03-17 | H. Lundbeck A/S | Alcohol derivatives of carboxamides as Kv7 potassium channel openers |
| CN111727182A (en) * | 2018-02-20 | 2020-09-29 | H.隆德贝克有限公司 | Alcohol derivatives as Kv7 potassium channel openers |
| JP2021519814A (en) * | 2018-02-20 | 2021-08-12 | ハー・ルンドベック・アクチエゼルスカベット | Alcohol derivative as Kv7 potassium channel opener |
| JP7121144B2 (en) | 2018-02-20 | 2022-08-17 | ハー・ルンドベック・アクチエゼルスカベット | Alcohol derivatives as Kv7 potassium channel openers |
| US11434199B2 (en) | 2018-02-20 | 2022-09-06 | H. Lundbeck A/S | Alcohol derivatives as KV7 potassium channel openers |
| CN111727182B (en) * | 2018-02-20 | 2023-05-26 | H.隆德贝克有限公司 | Alcohol derivatives as Kv7 potassium channel openers |
| EP4241843A3 (en) * | 2018-02-20 | 2023-09-27 | H. Lundbeck A/S | Alcohol derivatives as kv7 potassium channel openers |
| US11548849B2 (en) | 2019-08-02 | 2023-01-10 | H. Lundbeck A/S | Alcohol derivatives as KV7 potassium channel openers |
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Application publication date: 20160615 |