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WO2008006276A1 - INHIBITEUR À PETITE MOLÉCULE POUVANT INHIBER LA FIBROSE DU POLYPEPTIDE Aβ DANS LA MALADIE D'ALZHEIMER, PROCÉDÉS DE PRÉPARATION CORRESPONDANTS, COMPOSITIONS PHARMACEUTIQUES ET UTILISATIONS CORRESPONDANTES - Google Patents

INHIBITEUR À PETITE MOLÉCULE POUVANT INHIBER LA FIBROSE DU POLYPEPTIDE Aβ DANS LA MALADIE D'ALZHEIMER, PROCÉDÉS DE PRÉPARATION CORRESPONDANTS, COMPOSITIONS PHARMACEUTIQUES ET UTILISATIONS CORRESPONDANTES Download PDF

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WO2008006276A1
WO2008006276A1 PCT/CN2007/001518 CN2007001518W WO2008006276A1 WO 2008006276 A1 WO2008006276 A1 WO 2008006276A1 CN 2007001518 W CN2007001518 W CN 2007001518W WO 2008006276 A1 WO2008006276 A1 WO 2008006276A1
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group
compound
halogen
acid
phenyl
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PCT/CN2007/001518
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English (en)
Chinese (zh)
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Dongxiang Liu
Yechun Xu
Hong Liu
Yu Zhou
Xu Shen
Kaixian Chen
Hualiang Jiang
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Publication of WO2008006276A1 publication Critical patent/WO2008006276A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the field of medicinal chemistry, and more particularly to beta-amyloid associated with Alzheimer's disease.
  • Inhibitor of protein ( ⁇ ) More specifically, the present invention relates to a novel class of compounds having a symmetric structure (Formula I) which inhibit the aggregation and fibrosis of ⁇ -amyloid, or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof;
  • a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, and the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention and treatment of Alzheimer's disease application.
  • Background technique
  • AD Alzheimer's disease
  • AD patients The cause of dementia in AD patients is due to the death of neuronal cells in certain areas of the human brain due to high levels of "senile plaques, and "neurofiber disorders.”
  • the main hallmark of Alzheimer's disease is cerebrovascular disease.
  • the formation of insoluble amyloid (A/3 peptide), the abnormal production and deposition of A ⁇ is considered to be one of the main causes of neuronal damage and loss.
  • ⁇ is a 39-43 amino acid polypeptide catalyzed by ⁇ - and ⁇ -secretase from the 5-amyloid precursor protein, and its main forms are ⁇ 40 and ⁇ 42.
  • the results show that the production of A ⁇ is the most critical factor in the early stage of AD. In the early stage of AD, the overproduction of ⁇ 42 directly causes its pathological stratification, and the excess ⁇ 42 is difficult to be removed, so ⁇ 42 will be deposited under the influence of some aggregation factors. In theory, as long as the expression of sputum is blocked, the formation of ⁇ can be avoided and the purpose of treating AD can be achieved.
  • ⁇ -secretase pathway In normal In the case ( ⁇ -secretase pathway), APP is catalytically hydrolyzed by the ⁇ -secretase into the soluble purine fragments ⁇ -APPs and C83 peptides within the A ⁇ sequence, which prevents the formation of A ⁇ ; in the abnormal case ( ⁇ -secretion) Enzyme pathway), ⁇ is catalyzed by ⁇ -secretase in the ⁇ -terminal cleavage of ⁇ to form soluble ⁇ fragment ⁇ -APPs and C99 peptide, which is cleavage by ⁇ -secretase at the C-terminus of ⁇ to complete ⁇ .
  • ⁇ -secretase is the rate-limiting enzyme that produces ⁇ , which is a prerequisite for the catalyzed hydrolysis of hydrazine to ⁇ .
  • ⁇ polypeptide molecules Before the ⁇ polypeptide molecule was cleaved from the sputum, 12 to 14 amino acid residues at the C-terminus were folded in the a-helical form in the cell membrane; 28 residues at the N-terminus were exposed outside the membrane, and the structure was unknown.
  • the ⁇ polypeptide molecule is cleaved from the APP by ⁇ -secretase and ⁇ -secretase, the C-terminal helically folded form will be opened.
  • ⁇ polypeptide molecules may aggregate into fibers via a random structure (RC) ⁇ -sheet or 2 a-helix ⁇ -sheet pathway.
  • RC random structure
  • the conformation of the A ⁇ polypeptide molecule varies with the environment of the solution in which it is placed.
  • aqueous solution In aqueous solution, it exists in the form of a random structure, a ⁇ -sheet and an a-helical mixed conformation.
  • the A ⁇ polypeptide is present in the a-helical conformation form in an aqueous solution of SDS or a solution of fluorinated alcohol in a simulated membrane environment.
  • Molecular dynamics simulations and experiments have shown that the ⁇ polypeptide molecules fold and aggregate into fibers, and undergo a conformation of stable intermediates containing a-helix.
  • the NMR structure indicated that the ⁇ peptide was folded into two a-helical structures in TFE, SDS and HFIP, and a flexible loop region was connected between the two a-helices.
  • the length of the a-helix formed by the ⁇ polypeptide in these solutions is different, indicating that the ⁇ polypeptide is flexible in structure and depends on the solution environment. Since the solution used in nuclear magnetic resonance experiments differs greatly from the physiological environment, these structures of the A ⁇ polypeptide cannot be directly used to design inhibitor molecules.
  • ⁇ polypeptide requires the participation of metal ions Zn 2+ and Cu 2+ .
  • Certain ⁇ -peptide inhibitors such as Clioquinol, bind to these metal ions and dissolve the deposited proteins in the brain. ⁇ can also prevent the aggregation of ⁇ monomer molecules.
  • Clioquinol is used in combination with vitamin B 12 and has entered Phase II clinical trials.
  • Other ⁇ inhibitors that have been reported have not entered clinical trials due to toxicity, degradation by proteases in the body, and inability to cross the blood-brain barrier, and further chemical structural modifications and optimizations are needed.
  • the invention adopts a stable intermediate conformation in the process of ⁇ folding as a target, and uses a computer to virtually screen, design and synthesize a kind of d, molecular inhibitor which has a new chemical structure skeleton to prevent fibrosis of ⁇ polypeptide. Summary of the invention
  • the invention adopts the nuclear magnetic resonance structure (PDB number: 1BA4) of the ⁇ 40 polypeptide in the aqueous solution of SDS as the initial conformation, and uses the Biopolymer module in Sybyl6.8 to hydrogenate the ⁇ 40 polypeptide molecule and the Kollman-all-atom charge, using Gromac software.
  • Molecular dynamics simulations were performed on peptide molecules to study their conformational changes.
  • ⁇ polypeptides can exist as stable structures of ⁇ -helix/ ⁇ -sheets (Xu, Y, Shen, J., Luo, X., Zhu, W., Chen, K., Ma, J., and Jiang, H. (2005) Conformational transition of amyloid beta-peptide.
  • the present inventors used the autoMS and sphgen programs in the DOCK 4.0 software package to describe the entire molecular surface of the ⁇ -helix/ ⁇ -sheet stable intermediate structure of the ⁇ 40 polypeptide molecule, and to integrate the globules on the surface of the molecule.
  • As the target active site for screening. determine the calculation range of the GRID program, calculate the hydrophobicity, electrostatic interaction, van der Waals interaction and other properties of the molecular surface on the surface grid points of the ⁇ 40 polypeptide molecule, and save the grid point data to speed up the calculation of the scoring evaluation in the molecular docking process. .
  • SPECS compound data The compounds in the library were placed into the active site using the DOCK4.0 program.
  • the main screening parameters for DOCK 4.0 were set to: configuration per circle: 30; anchor orientation: 50 Energy minimization : 100; energy minimization circle: 1 .
  • the binding of the compound to the ⁇ 40 polypeptide molecule is evaluated by contact scoring and chemical scoring evaluation functions. We took the top 1000 compounds with the best scores for bioactivity screening.
  • Another object of the present invention is to provide a process for the preparation of a compound of the above formula I.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide a compound of the formula I or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention and treatment of Alzheimer's disease, i.e., against Alzheimer's disease.
  • the present invention provides a compound having a symmetrical structure of the following formula I or a pharmaceutically acceptable salt thereof:
  • ⁇ is 0, ⁇ or S; Can be aromatic, Or / 5 , where Z is OH, SH or N3 ⁇ 4;
  • R4 and R 5 are each hydrogen, saturated C1-C6 straight-chain or branched-chain or unsaturated hydrocarbon group, a saturated or unsaturated cycloalkane group, an aromatic group, or a 5-7 membered heterocyclyl group;
  • the aromatic group may be a phenyl group, a substituted phenyl group, a naphthyl group or a biphenyl group, a 5-7 membered aromatic heterocyclic ring, wherein the substituted phenyl group may include 1 to 4 substituents, and the substituent may be selected from halogen, C1-C6 straight a chain or branched hydrocarbon group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxy group, a trifluorodecyl group, a trifluoromethoxy group, a carboxyl group, a C1-C4 alkoxy group, a fluorenyl group, and a C1
  • the halogen is fluorine, chlorine, bromine or iodine
  • the aryl group may be a phenyl group, a substituted phenyl group, a naphthyl group or a biphenyl group, a 5-7 membered aromatic heterocyclic ring; wherein the substituted phenyl group may include 1 to 4 substituents, and the substituent may be optionally From halogen, C1-C6 linear or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 alkoxy, fluorenyl and C1 -C4 acyl; the 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and optionally containing one or more selected from halogen, C1-C6 straight chain or Branched hydrocarbon group, cyano group, nitro group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluorometh
  • the pharmaceutically acceptable salt of the compound of the formula I provided by the present invention may specifically be exemplified by propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid or citric acid.
  • a salt formed with an acidic base such as an organic acid or aspartic acid or glutamic acid to form an ester, such as a sodium, potassium, calcium, aluminum salt and an ammonium salt
  • a salt formed with an organic base such as guanamine a salt, an ethylamine salt, an ethanolamine salt or the like
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid which is esterified with a basic amino acid such as lysine, arginine or ornithine.
  • a salt, or a salt with an organic acid such as citric acid, acetic acid, picric acid, sulfonic acid, ethanesulfonic acid or the like.
  • a preferred embodiment of the compound of formula I of the present invention is a compound having the structure: or a pharmaceutically acceptable salt thereof:
  • W is Y is 0; is a phenyl group or a substituted phenyl group;
  • R 3 is selected from the group consisting of hydrogen, halogen, fluorenyl and ethyl;
  • a second preferred embodiment of the compound of the formula I of the present invention is a compound having the structure: or a pharmaceutically acceptable salt thereof:
  • W is ⁇ is 0; is ⁇ R 4 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, decyl and ethyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, fluorenyl and ethyl;
  • anthracenyl group is selected from the group consisting of an anthracenyl group, a morphinolyl group, a methylpiperazinyl group, a phenyl group and a substituted phenyl group; and Z is a hydroxyl group.
  • W is +( ⁇ 3 ; ⁇ is 0; 1 1 is / R 5 ;
  • R 2 is selected from the group consisting of hydrogen, a metal, a methyl group and an ethyl group;
  • R 3 is selected from the group consisting of hydrogen, halogen, methyl and ethyl
  • R 5 is selected from the group consisting of phenyl, substituted phenyl, thienyl and furanyl;
  • a fourth preferred embodiment of the compound of the formula I of the present invention is a compound having the structure: or a pharmaceutically acceptable salt thereof:
  • W is Y is NH; of ⁇ R4;
  • R 2 is selected from the group consisting of hydrogen, halogen, decyl and ethyl;
  • a fifth preferred embodiment of the compound of formula I according to the invention is a compound having the structure or a pharmaceutically acceptable compound thereof, selected from the group consisting of fluorenyl, morphinolyl, decylzinyl, phenyl and substituted phenyl; Salt: in formula (I), Y is 0; is phenyl or substituted phenyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, decyl and ethyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, fluorenyl and ethyl;
  • a sixth preferred embodiment of the compound of the formula I of the present invention is a compound having the structure: or a pharmaceutically acceptable salt thereof: in the formula (I), ⁇ is 0; R 5 R 2 is selected from the group consisting of hydrogen, halogen, decyl and ethyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, fluorenyl and ethyl
  • R 5 is selected from the group consisting of phenyl, substituted phenyl, thienyl, furyl
  • a seventh preferred embodiment of the compound of the formula I of the present invention is a compound having the structure: or a pharmaceutically acceptable salt thereof: in the formula (I), W is; Y is 0;
  • 'R 2 is selected from the group consisting of hydrogen, halogen, fluorenyl and ethyl;
  • R 5 is selected from the group consisting of phenyl, substituted phenyl, thienyl, furyl;
  • W is -CH 2 -; Y is O;
  • R 2 is selected from the group consisting of hydrogen, halogen, decyl and ethyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, methyl and ethyl
  • R 5 is selected from the group consisting of phenyl, substituted phenyl, p-secenyl, furyl;
  • the present invention provides a process for the preparation of a compound of the formula I and an intermediate thereof, wherein R
  • R 3 , W, and Y are as follows:
  • the method includes the following steps:
  • compound (II) is catalyzed by concentrated hydrochloric acid to obtain compound (III); Among them, acetone, 1,1, 1,3,3,3-hexafluoroacetone, cycloalkanone, and the like can be mentioned.
  • III which may be acetone, 1,1,1,3,3,3-hexafluoroacetone, cycloalkanone, etc.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the medicine may further comprise an odorant, a fragrance, etc.
  • a desirable ratio of the pharmaceutical composition provided by the present invention is that the compound of the formula I or a pharmaceutically acceptable salt thereof is present as an active ingredient in an amount of from 65% to 99.5% by weight based on the total weight, and the balance is from 0.5 to 35% by weight based on the total weight. Or preferably more preferably from 1 to 20%, or preferably from 1 to 10%, of a pharmaceutically acceptable carrier, diluent or solution or salt solution.
  • the compound provided by the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof can be used in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be present in a suitable form.
  • the solid or liquid carrier or diluent is neutralized in a suitable sterilizing device for injection or drip.
  • compositions thereof can be prepared according to conventional methods of preparation in the pharmaceutical arts.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutical composition can be used clinically for mammals, including humans and animals, and can be administered through the mouth, nose, skin, lung, or gastrointestinal tract. Most preferably oral.
  • the best recommended daily dose is 0.01-200 mg/kg body weight, taken at once, or 0.01-100 mg/kg body weight.
  • the optimal dosage for the individual should be based on the specific treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found.
  • BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the incorporation of an organic small molecule inhibitor onto an A ⁇ polypeptide to prevent it from forming ⁇ -sheets and fibrosis;
  • Figure 2 illustrates the binding of the compound DC-AB1 to the A ⁇ polypeptide, wherein the ⁇ 40 polypeptide molecule for virtual screening contains a stable structure of ⁇ -helix/ ⁇ -sheet; ⁇ ) The designed small molecule inhibitor DC-AB1 is bound to The C-terminal ⁇ -sheet region of the ⁇ 40 polypeptide molecule; C) the specific mode of action of DC-AB1 binding to the amino acid residue of the ⁇ 40 polypeptide; Figure 3 illustrates that compound DC-AB1 inhibits fibrosis of ⁇ 42 polypeptide in a concentration-dependent manner;
  • Figure 4 shows that the incubation experiment at 20 °C for 20 hours confirmed that DC-AB1 inhibited the formation of ⁇ polypeptide fibrosis
  • data I, II, III, IV, V were 2 ⁇ 5 ⁇ 200 ⁇ ⁇ 42 and 0 ⁇ , 10 ⁇ , 20 ⁇ L, respectively.
  • Figure 7 is a graph showing the change in the conformation of ⁇ 40 caused by the binding of compound DC-AB1 to ⁇ 40 polypeptide by circular dichroism. detailed description
  • the 1-chloro-2-propanol in the step 1.3 of the first embodiment is replaced with furan-2-indoloyl chloride, and the remaining raw materials, reagents and preparation methods are the same as those in the first embodiment, and the product 2,2-di[3,5 is obtained. -Dibromo-4-furanyl-2-indoloyloxyphenyl]propane.
  • the binding of the compound DC-AB1 to the A ⁇ 40 polypeptide is shown in Figure 2.
  • the compound binds mainly to the A ⁇ polypeptide molecule by hydrophobic interaction.
  • the two aromatic ring groups of DC-AB1 bind to the Val-24, Gly-29, Val-40 amino acid residues of the A ⁇ polypeptide molecule, respectively.
  • the morphinin group of DC-AB1 binds to the hydrophobicity of Val-40 and Leu-34 of the polypeptide molecule.
  • the site Fig. 2C
  • Thioflavin T has a maximum fluorescence emission wavelength shifted from 435 rnn to 482 nm after binding to fibrinated ⁇ polypeptide, and the fluorescence intensity correlates with the amount of fibrotic ⁇ polypeptide it binds.
  • the stronger the binding ability of the compound to the A ⁇ polypeptide the less the amount of fibrotic A ⁇ polypeptide present in the solution in free form, and the weaker the fluorescence emission intensity of Thiofenin in the vicinity of 482 nm due to the binding of the fibrotic polypeptide.
  • the ⁇ 42 polypeptide (purchased from Sigma-Aldrich, USA, product number A-9810) was dissolved in DMSO to prepare a solution having a concentration of 200 ⁇ .
  • the ⁇ 42 solution was centrifuged at 12,000 rpm for 10 minutes at high speed, and the supernatant was taken for experimentation.
  • the small molecule inhibitor DC-AB1 of the present invention was dissolved in DMSO to prepare a series of different concentrations of 0.1 - 10 mM.
  • the concentration of ⁇ 42 in the reaction solution was 2.5 ⁇ , and the concentration of DC-AB1 required to prevent half-concentration of ⁇ 42 fibrosis was 35.6 ⁇ , that is, 14.24 times the amount of the compound required to prevent fibrosis of the half concentration of ⁇ 42.
  • Compound DC-AB1 inhibits the formation of fibrosis of ⁇ 42 polypeptide
  • the inhibition of ⁇ 42 polypeptide fibrosis by DC-AB1 was also confirmed by a 20-hour incubation experiment.
  • the reaction system was incubated in a water bath at 37 ° C for 20 hours. Further, ⁇ 7.5 ⁇ ThT (in PBS) was added, and the intensity of fluorescence emission at an excitation wavelength of 430 nm and 483 nm was measured.
  • the experiment was performed on a Hitachi F-2500 fluorometer with a PMT setting of 700 and a reaction time of 0.08 seconds.
  • the fluorescence intensity measured from the ⁇ 42 reaction system was approximately 2,700 RFU (data I) after 20 hours of incubation in the absence of inhibitor.
  • the fluorescence intensity also decreases to approximately U00 RFU (data II ⁇ V).
  • the formation of ⁇ 42 fibers was reduced, and the presence of DC-AB1 significantly inhibited the formation of ⁇ polypeptide fibrosis.
  • Fig. 5A is an image of ⁇ 42 observed under an atomic force microscope in the absence of the compound DC-AB1, and it can be clearly seen that ⁇ 42 aggregates to form fibers.
  • Figure 5 ⁇ is the image seen after incubation of ⁇ 42 with compound DC-AB1. In contrast to Figure 5, it can be clearly seen that the compound DC-AB1 inhibits the formation of ⁇ 42 fibers.
  • Freshly prepared ⁇ 42 (without incubation) was added to the first sample cell, and a black band of ⁇ 42 monomer was observed.
  • the third sample cell was filled with ⁇ 42 alone in the absence of DC-AB1. , did not see the black band of the monomer, indicating that ⁇ 42 has been aggregated into a large molecular weight fiber or multimer; and the second sample cell is added with a sample of ⁇ 42 incubated in the presence of DC-AB1, it can be seen that ⁇ 42 still It exists in the form of a monomer to an oligomer. From this electropherogram, the inhibition of ⁇ 42 fibrosis by DC-AB1 can be clearly seen.
  • the ⁇ -helical conformation of ⁇ 40 increased significantly after the addition of 20% TFE, because the low-polarity solvent of TFE can dissociate the hydrogen bond of ⁇ -sheet and stabilize the ⁇ -helical structure of the protein.
  • the ⁇ -helix content of ⁇ 40 in 20% TFE was significantly decreased, while the conformation of ⁇ -sheet was increased, which was expressed in the bottom peak of 208 nm which characterizes the ⁇ -helical conformation.
  • the 220 nm is weakened, and a characteristic peak characterizing the ⁇ -sheet conformation appears at 216 nm. This further demonstrates that DC-AB1 binds to ⁇ 40, and depolymerizes the ⁇ -helix of ⁇ 40, causing it to form a ⁇ -fold. Stack.
  • the preparation method of the compound of the general formula I of the present invention has the advantages of mild reaction conditions, easy availability of raw materials, operation and post-treatment of a single cylinder.
  • the compound of the general formula I of the present invention exhibits an activating/inhibiting enzyme activity in a computer virtual screening and a ⁇ -secretase binding assay, and can effectively treat and prevent Alzheimer's disease, children with mental retardation, amnesia and others. Heart and brain tube disease.
  • the compounds of the invention are very toxic.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for the preparation of a medicament for treating or preventing a disease caused by secretion of a enzyme.

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Abstract

La présente invention concerne un type de nouveaux composés qui présentent la structure symétrique représentée par la formule I et qui peuvent inhiber l'agrégation et la fibrose de la protéine β-amyloïde, leurs sels pharmaceutiquement acceptables et des procédés de préparation de ces derniers. La présente invention concerne également les compositions pharmaceutiques contenant ces composés ou leurs sels pharmaceutiquement acceptables et les utilisations de ces composés ou de leurs sels pharmaceutiquement acceptables ou encore des compositions pharmaceutiques pour préparer un médicament destiné à la prévention ou au traitement de la maladie d'Alzheimer. Les composés ou leurs sels pharmaceutiquement acceptables présentés dans cette invention peuvent inhiber l'agrégation et la fibrose de la protéine β-amyloïde par combinaison avec le polypeptide Aβ. Ces composés peuvent par conséquent être utilisés pour prévernir ou traiter les maladies d'Alzheimer.
PCT/CN2007/001518 2006-07-03 2007-05-09 INHIBITEUR À PETITE MOLÉCULE POUVANT INHIBER LA FIBROSE DU POLYPEPTIDE Aβ DANS LA MALADIE D'ALZHEIMER, PROCÉDÉS DE PRÉPARATION CORRESPONDANTS, COMPOSITIONS PHARMACEUTIQUES ET UTILISATIONS CORRESPONDANTES WO2008006276A1 (fr)

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