CN102372703A - Indole benzothiazole derivative and pharmaceutical use thereof - Google Patents

Indole benzothiazole derivative and pharmaceutical use thereof Download PDF

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CN102372703A
CN102372703A CN2010102561248A CN201010256124A CN102372703A CN 102372703 A CN102372703 A CN 102372703A CN 2010102561248 A CN2010102561248 A CN 2010102561248A CN 201010256124 A CN201010256124 A CN 201010256124A CN 102372703 A CN102372703 A CN 102372703A
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acceptor
receptor
indoles
analog derivative
compound
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付伟
镇学初
杜鹏
刘慧芳
沈庆
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Abstract

The invention, belonging to the field of biological pharmacy, relates to an indole benzothiazole derivative and an application of the derivative for preparing inhibitors of 5-HT receptor, especially an application in the field of medicines of nerve system diseases related to the 5-HT receptor. The test of bioactivity shows the indole benzothiazole derivative has inhibiting effect on the 5-HT receptor related to the pathological mechanism of nerve system diseases. The derivative can be used as a medical precursor for synthesizing the inhibitor of the 5-HT receptor, further can be used for preparing medicines for schizophrenia, parkinsonism and other nerve system diseases caused by disfunction of the 5-HT system.

Description

Indoles benzothiazole analog derivative and pharmaceutical use thereof
Technical field
The invention belongs to field of biological pharmacy, relate to indoles benzothiazole analog derivative and pharmaceutical use thereof, be specifically related to indoles benzothiazole analog derivative and the purposes in preparation 5-HT acceptor inhibitor thereof, relate in particular to indoles benzothiazole analog derivative 5-HT 1AThe avidity of acceptor and action characteristic and in preparation nervous system disorders medicine, the application of particularly relevant nervous system disorders pharmaceutical field with the 5-HT acceptor.
Background technology
One of clinical modal great spirit type disease is schizophrenia (schizophrenia), and this illness is a kind of lasting, chronic disease, and its clinical manifestation comprises positive symptom and negative symptoms, and wherein positive symptom comprises illusion, vain hope, chorea etc.; Negative symptoms is mainly pointed out and is known functional impairment, learning memory disorder, working memory obstacle etc.The continuous increase of Along with people's work and life stress, spiritual problem produces serious detrimentally affect to entire society.Early stage first-generation antischizophrinic thing is main with the treatment positive symptom, and is very poor to the curative effect of negative symptoms, and EPS (Extrapyramidal Symptoms, incidence height EPS).S-generation antischizophrinic thing is representative with the leoponex; This medicine has better curative effect to the schizophrenia positive symptom; Cognition dysfunction also there is certain improvement, tangible EPS and dyspraxia can take place, but in clinical use; Part patient can cause serious granulocytopenia, have in addition the lethality granulopenia takes place.Therefore, the non-classical psychotroptic drug of the s-generation of novel, the low toxic side effect of development structure is very necessary.
Research shows that schizoid pathogenic factor more complicated relate to inherited genetic factors, nature factor, psychological factor, environmental factors and organism physiology factor etc., but its pathogenesis is still indeterminate.Over past ten years, non-classical tranquilizer becomes the s-generation medicine that the serious Psychiatric disorders of treatment does not have EPS, and its complicated pluralism opinion mechanism of action is present main flow viewpoint.Wherein, part serotonin (5HT 1A) hypothesis of Dopamine HCL (DA) function of receptors gains universal acceptance in the agonist balance brain, its representative drugs is Aripiprazole (aripirazole).There is The extrapyramidal symptoms in this medicine, delirium, shock, spinoffs such as dysfunction of liver.Thereby development of new 5HT 1AReceptor-ligand is significant to research and development high-efficiency low-toxicity spinoff novel anti schizophrenia drug.
The area of computer aided medicinal design is through aids drug and the macromolecular interaction of receptor biological or analyze and have medicines structure and active internal relation, the appropriate design compound, its efficiently the lead compound ability of discovery extensively approved.Traditional only depend on the X-ray structure or the homology mould established model of acceptor usually, but because albumen has flexibility in vivo, single receptor model can not reflect the true activity conformation when acceptor combines with all parts based on the receptor structure medicinal design.
Summary of the invention
The purpose of this invention is to provide indoles benzothiazole analog derivative and pharmaceutical use thereof, be specifically related to indoles benzothiazole analog derivative and the purposes in preparation 5-HT acceptor inhibitor thereof, relate in particular to indoles benzothiazole analog derivative 5-HT 1AThe avidity of acceptor and action characteristic and at preparation nervous system disorders medicine, particularly relevant with 5-HT acceptor nervous system disorders medicine is like the application in antischizophrinic thing field.
The present invention is with the higher suprarenin β of homology 2The acceptor crystalline structure is that template has made up Dopamine Receptors and 5HT receptor model; And these models are carried out molecular dynamics simulation, and means of molecular dynamics simulation technique is combined with method based on receptor agents pharmacophoric group model, through means of molecular dynamics simulation technique; Produce a series of protein conformations; Carry out the conformation cluster analysis, and the typical conformation that extracts each cluster carries out avtive spot and survey, make up the dynamic Pharmacophore Model that takes into full account the flexible and chemical property of acceptor; Searching for known chemical storehouse, providing of the present invention has highly active micromolecular compound to the 5HT acceptor.
The present invention carries out through following technical proposals:
With suprarenin β 2The acceptor crystalline structure is a template, makes up 5-HT 1AReceptor model; The accuracy of receptor model is verified and carried out molecular dynamics simulation to obtain the flexible conformation of acceptor; The flexible conformation of acceptor is carried out avtive spot to be surveyed; Superimposed result of detection also makes up the dynamically group's of effect model of acceptor; Screening known compound DB is also tested its activity, obtains the indoles benzothiazoles derivative compound of formula I structure, and through the biological activity test experiment confirm, said compound is to 5-HT 1AIt is active that acceptor has good inhibition, can be further used for preparing the medicine of the treatment nervous system disorders relevant with the 5-HT acceptor.
Compound according to the invention has formula I structure:
Figure 563697DEST_PATH_IMAGE001
In the formula
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8For H, the alkyl that contains 1-4 carbon, hydroxyl, halogen, contain the acyl group of 1-4 carbon;
X is C, N;
But compound of the present invention comprises its medication salt and hydrate.
The present invention tests through biological activity test, and the result shows, described compound pair and the closely-related 5-HT of the pathology of neural psychosis 1AAcceptor has restraining effect.Described neural psychosis comprises schizophrenia and parkinsonism and dysthymia disorders etc.
Formula I compound of the present invention can be used as lead compound, carries out structure of modification, and preparation and synthetic new 5-HT acceptor inhibitor are used to treat neural psychosis.
Formula I compound of the present invention and medicine salt thereof or hydrate can be used for preparing the schizophrenia that treatment causes by the disorder of 5-HT system function or the medicine of anti-Parkinson disease.
For the ease of understanding, below will describe in detail the present invention through concrete accompanying drawing and embodiment.What need particularly point out is; Specific examples and accompanying drawing only are in order to explain; Obviously those of ordinary skill in the art can explain according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Description of drawings
Fig. 1 is serotonin 5HT 1AThe acceptor 3 d structure model
Fig. 2 a is 5HT 1AThe dynamic Pharmacophore Model of acceptor, redness, cyanogen look, red-purple and green are represented the positive electric group of pharmacophore, hydrophobic grouping, hydrogen-bond donor group and hydrogen bond receptor group respectively; B is 5HT 1ARelativity pattern between the Key residues of acceptor pharmacophore and acceptor.
Embodiment
Embodiment 1 5-HT 1AMade up by body three-dimensional models
Protein sequence is from Swiss-Prot DB (http://www.expasy.ch/sprot/), the plain β of human adrenal gland 2Acceptor and 5-HT 1AThe serial number of acceptor is respectively P07550 and P08908.ClustalW algorithm in the employing FASTA program is with 5-HT 1AAcceptor and suprarenin β 2The sequence of acceptor is carried out the multiple sequence comparison, according to the position of conserved residues in the GPCR superfamily matching sequence is finely tuned then, and the result is as shown in table 1.5-HT 1AAcceptor and suprarenin β 2The homology of acceptor transbilayer helix is 41.9%.
The 1st, 5-HT 1AAcceptor and suprarenin β 27 of acceptors are striden the homology and the similarity in film district.
Table 1
? Homology Similarity
TM-1 25.0% 53.1%
TM-2 40.4% 76.7%
TM-3 52.9% 79.4%
TM-4 24.0% 52.0%
TM-5 36.4% 84.8%
TM-6 68.8% 84.4%
TM-7 41.7% 66.7%
Total 41.9% 61.0%
With suprarenin β 2Acceptor (Rasmussen SGF, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, et al. Nature2007; 450 (7168): 383-U4. PDB number is 2RH1) be template, adopt Modeller 9v2 program construction 5-HT 1AThe acceptor 3 d structure model.It comprises following key step: 1) connect according to sequence and join the conservative region that the result confirms acceptor; 2) with conserved regions suprarenin β 2The coordinate of the C α of acceptor is given target recipient, and generates rational side chain conformation at random; 3) 10 candidate structure in generation Loop district, and according to lowest mean square root and the suitable loop conformation of only geometrical matching principle selection; 4) Gly with some amount replaces flexible bigger ICL-3 to connect TM-6 and TM-7; 5) (Tripos Inc, St. Louis MO) make up conservative disulfide linkage between TM-3 and ECL-2, and adopt the Kollman All-Atom field of force that three models are carried out the progressively energy-optimised of 500 steps respectively with Sybyl 6.9 softwares; 6) with Procheck 3.5.4 program the model of gained is verified.Procheck result shows: the 5-HT after the optimization 1AAcceptor has 90.5% amino acid to be positioned at ramachandran map Ramachandran (Ramachandran plot).
Embodiment 25-HT 1AAcceptor blooming molecular dynamics simulation
Use the GROMACS 3.3.1 and the GROMOS96 field of force to carry out molecular dynamics simulation.5-HT after preliminary energy-optimised 1AReceptor model vertically inserts in POPC (palmitoyl-oleoyl-phosphatidylcholine) phospholipid bilayer.Albumen and POPC structural models are dissolved in single-point electric charge (SPC) the water molecules model; Application of B erendsen constant temperature method makes system temperature maintain 300K; The pressure of system remains on a normal atmosphere; All comprise the bond distance of Wasserstoffatoms chemical bond with the LINCS algorithm limits; Electrostatic interaction calculates through particle-mesh Ewald (PME) method, with 9
Figure 822378DEST_PATH_IMAGE002
be cutoff value (cut off); The interactional cutoff value of Lennard-Jones elect as 14
Figure 214045DEST_PATH_IMAGE002
.For each simulated system; All use a cubes box as analogue unit; Protein is placed on the box center; And guarantee any position of protein surface to the distance of any one face of box greater than 10
Figure 41974DEST_PATH_IMAGE002
, thereby avoid protein to interact with the protein in the cycle mirror image.Periodic final condition (PBC) in the simulation process.Use Na +Perhaps Cl -The whole system of balance, the system total charge of making are 0.The optimal way that employing is graduallyed relax control: (1) fixing protein and POPC structure, optimize water molecules and ion; (2) fixing protein is optimized POPC, water molecules and ion; (3) fixing protein main chain is optimized other all atoms; (4) fixation of C alpha atom is optimized other atoms; (5) at last whole system is optimized.Whole system is heated up according to 10K, 50K, 100K, 200K, 300K gradually; At last, to each system balance 500ps, adopt the NPT canonical ensemble to carry out the 100ns molecular dynamics simulation, every 1ps preserves a conformation.
5-HT 1AThe RMSD value of acceptor C alpha atom shows that albumen conformational change in initial 5ns is bigger, tends towards stability basically behind the 10ns.Corresponding therewith, the total energy of system also tends towards stability behind 10ns, thereby the explanation system has transitted to metastable conformation attitude.Adopt the GROMOS clustering algorithm that the conformation with similar structures that dynamics simulation obtains is classified as cluster, when cutoff value is made as 0.15nm, 5-HT 1AReceptor receptor obtains 25 group varietys (cluster); Cluster_ID and time diagram show; More preceding 10 group varietys of structure all are between the 6ns～100ns of structure and energy stabilization, therefore, extract the representative conformation of preceding 10 group varietys and set up dynamic pharmacophoric group model.
Embodiment 35-HT 1AThe avtive spot detection of acceptor and the structure of dynamic Pharmacophore Model.
The representative conformation of getting preceding 10 group varietys among the dynamics simulation result will be guarded Asp as receptor model 3.32On every side 10
Figure 773169DEST_PATH_IMAGE002
Zone definitions in the scope is the box that GRID program site is surveyed.Because GPCR acceptor pocket is electronegativity, chooses four kinds of typical probe: N+ (positive electric probe), O (hydrogen bond receptor probe), N1 (hydrogen-bond donor probe) and DRY (hydrophobic grouping probe) and survey corresponding negative electricity, hydrogen-bond donor, hydrogen bond receptor and hydrophobic chemical environment in the protein respectively.By the spy point that superimposed 10 conformations of C α obtain, visit the bound energy of point and choose suitable group variety according to GRID with the interactional character of acceptor amino acid residue, calculate the geometric centre and the rotation radius of group variety.
Use the View Hypothesis module of Catalyst to set up pharmacophore according to GRID result.Pharmacophoric group is selected Functions Only, and the corresponding pharmacophoric group of positive electricity, hydrogen-bond donor, hydrogen bond receptor and hydrophobicity selects POS CHARGE (pos), HB DONOR (HBD), HB ACCEPTOR (HBA) and HYDROPHOBIC (DRY) respectively.Acceptor Key residues location definition excluded volume (Excluded Volume; EX), radius be made as 1.5 .Dynamically pharmacophore and with the interaction of acceptor Key residues shown in Fig. 2 a and Fig. 2 b.
Embodiment 4Virtual screening and biological activity test based on the dynamic pharmacophore of acceptor
Use best flexible method search MayBridge DB (containing 61602 compounds) in the Catalyst CatSearch module; Dock with acceptor with matching value (Fit Value), the small molecules of pharmacophore according to small molecules; The xscore scoring functions; And small molecules ADMET property prediction result, from above-mentioned DB, select 10 candidate compounds and carry out active testing.
Dopamine D 2, D 3And 5-HT 2AThe receptor positive reference substance is Spiperone, 5-HT 1AThe receptor positive reference substance is 5-HT.Receive reagent thing and positive drug all to be dissolved to 0.01 mol/L, be diluted to 100 umol/L with deionized water then with DMSO.Testing compound and each 10 ul of radioactive ligand and 80 ul receptor proteins are added in the reaction tube, make test-compound and positive drug final concentration be 10 umol/L, after 15 min are hatched in 37 ℃ of water-baths, move to ice bath at once and stop its reaction; On Millipore cell sample scoop, through the quick suction filtration of GF/B glass fiber filter paper, and with elutriant (50 mM Tris-HCl; PH 7.7) 3 ml washing 3 times; With microwave oven 8 ~ 9 min oven dry, filter paper is moved in the 0.5 ml centrifuge tube, add the fat-soluble scintillation solution of 500 ul.Lucifuge leaves standstill more than 30 min, and counting is measured radioactive intensity.Calculate each compound isotropic substance aglucon bonded is suppressed percentage, inhibiting rate is higher than the receptor binding assays that 90% compound carries out a series of concentration, confirms half amount of suppression (IC50 suppresses 50% positive control medicine and receptors bind required compound concentration).Every concentration determination two looped pipelines, each compound carries out independent experiment twice.The result shows that compound F 17-hydroxy-corticosterone DFWHF002 is to 5HT 1AHave the highly selective activity, it and positive drug to inhibiting rate, IC50 and the Ki value of acceptor shown in table 2, table 3 and table 4.
FDFWHF002
Table 2 compound F 17-hydroxy-corticosterone DFWHF002 is to dopamine D 2, D 3Acceptor, 5-HT 1A, 5-HT 2AThe inhibiting rate of acceptor.
Table 3 compound and positive reference substance are to the IC50 of corresponding acceptor.
Table 4 compound and positive reference substance are to the Ki value of corresponding acceptor.
 
Table 2
Figure DEST_PATH_IMAGE004
Table 3
Figure 631776DEST_PATH_IMAGE005
Table 4
Figure DEST_PATH_IMAGE006
Experimental result shows that compound F 17-hydroxy-corticosterone DFWHF002 of the present invention is to 5-HT 1AThe restraining effect of acceptor is obvious.Pathology closely related (Newman-Tancredi A, Assie MB, Leduc N, Ormiere AM, Danty N, Cosi C. in view of 5-HT acceptor and neural psychosis such as schizophrenia, parkinsonism and dysthymia disorders International Journal of Neuropsychopharmacology2005; 8: 341-356), therefore, compound involved in the present invention can be made the 5-HT acceptor inhibitor, is further used for preparation treatment schizophrenia, the medicine of parkinsonism and dysthymia disorders.

Claims (6)

1. the indoles benzothiazole analog derivative of formula I,
Figure DEST_PATH_IMAGE001
In the formula,
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8For H, the alkyl that contains 1-4 carbon, hydroxyl, halogen, contain the acyl group of 1-4 carbon;
X is C, N.
2. by the indoles benzothiazole analog derivative of the described formula I of claim 1, it is characterized in that said indoles benzothiazole analog derivative comprises its medicine salt and hydrate.
3. claim 1 or 2 the indoles benzothiazole analog derivative purposes in preparation 5-HT acceptor inhibitor.
4. by the purposes of claim 3, it is characterized in that described indoles benzothiazole analog derivative is as the lead compound preparation or synthesize the 5-HT acceptor inhibitor.
5. claim 1 or 2 the indoles benzothiazole analog derivative purposes in preparation treatment schizophrenia or parkinsonism medicine.
6. by the described purposes of claim 4, it is characterized in that described indoles benzothiazole analog derivative suppresses the activity of 5-HT acceptor.
CN2010102561248A 2010-08-18 2010-08-18 Indole benzothiazole derivative and pharmaceutical use thereof Pending CN102372703A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015014256A1 (en) * 2013-07-29 2015-02-05 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
CN106960118A (en) * 2017-02-23 2017-07-18 邹长林 α1The three-dimensional crystalline structure model and its method for building up of AR subtype proteins
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof
CN111533738A (en) * 2020-05-27 2020-08-14 中国药科大学 Compound containing indole structure or pharmaceutically acceptable salt thereof, preparation method and application

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015014256A1 (en) * 2013-07-29 2015-02-05 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof
CN106960118A (en) * 2017-02-23 2017-07-18 邹长林 α1The three-dimensional crystalline structure model and its method for building up of AR subtype proteins
CN106960118B (en) * 2017-02-23 2021-03-19 邹长林 α1Three-dimensional crystal structure model of-AR subtype protein and establishment method thereof
CN111533738A (en) * 2020-05-27 2020-08-14 中国药科大学 Compound containing indole structure or pharmaceutically acceptable salt thereof, preparation method and application

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Application publication date: 20120314