EP1893199A2 - Modulateurs du domaine pdz - Google Patents

Modulateurs du domaine pdz

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Publication number
EP1893199A2
EP1893199A2 EP06722837A EP06722837A EP1893199A2 EP 1893199 A2 EP1893199 A2 EP 1893199A2 EP 06722837 A EP06722837 A EP 06722837A EP 06722837 A EP06722837 A EP 06722837A EP 1893199 A2 EP1893199 A2 EP 1893199A2
Authority
EP
European Patent Office
Prior art keywords
atom
conect
leu
val
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06722837A
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German (de)
English (en)
Inventor
Mangesh Combinature Biopharm AG JOSHI
Hartmut Combinature Biopharm AG OSCHKINAT
Markus Combinature Biopharm AG SCHADE
Carolyn Combinature Biopharm AG VARGAS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forschungsverbund Berlin FVB eV
Original Assignee
Forschungsverbund Berlin FVB eV
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Filing date
Publication date
Application filed by Forschungsverbund Berlin FVB eV filed Critical Forschungsverbund Berlin FVB eV
Publication of EP1893199A2 publication Critical patent/EP1893199A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to novel substances which bind to the PDZ domain of proteins, uses of substances,. which bind to the PDZ domain of proteins, as well as means to identify compounds that bind to the PDZ domain of a protein.
  • the PDZ domain was originally identified as a common member in three structurally related proteins, PSD-95 / SAP90, DLG and ZO-I (Garner et al., TRENDS IN CELL BIOL., 6: 429-433 (1996)). Craven et al., CELL, 93: 495-498 (1998); Hutter et al., NEURO SCI Res., 32: 1-7 (1998)).
  • the PDZ domain is also called DLG Homologieregion
  • DHR Downlink Reduction Function
  • GLGF Repeat GLGF Repeat
  • the latter is due to the presence of a Gly-Leu-Gly-Phe sequence motif.
  • the PDZ domain comprises about 90 amino acids, and crystallographic studies on PSD-95, SAP97, and CASK show that it consists of two alpha helixes and six beta sheets
  • PDZ domains which occur 785 times in 436 different human genes, belong to one of the most important protein classes in the human genome (Kay et al., Chemistry & Biology, 11: 423- 424 (2004)). PDZ domains control the localization, clustering, recycling and cell membrane expression of many receptor, transport and ion channel proteins (Dev, KK, Nat., Rev. Drug Discov 3: 1047-1056 (2004)).
  • PDZ domains By recruiting downstream proteins into signaling pathways, PDZ domains mediate the formation of specific multi-protein complexes. Proteins containing PDZ domains play important roles in many key pathways, including maintenance of polarity and morphology of epithelial cells, organization of postsynaptic density in neural cells, and regulation of membrane protein activity and transport. It follows that substances which bind to the PDZ domain can specifically modulate such proteins or protein complexes and consequently have a particular therapeutic potential.
  • blocking of the second PDZ domain of the MAGI3 protein has been shown to be threefold by irreversible small molecule synthetic inhibitors Increasing the activity of a cancer-relevant enzyme in a cell culture model [Fujii et al., J. Am. Chem. Soc. 125: 12074-12075. (2003)).
  • the invention is therefore based on the technical problem of specifying compounds which are capable of binding to the PDZ domain of a protein where, in the absence of a modulator, the interaction with natural protein ligands takes place. Furthermore, the invention is based on the technical problem of specifying means for identifying such compounds.
  • the invention teaches the use of a compound according to formula I.
  • C1 to C5 includes alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl and neopentyl.
  • R 1 is -NO 2 or -Hal
  • R 2 and R 3 are the same or different and are -H or -Hal
  • -Hal is -F, -Cl, -Br, or -J
  • free valencies of the rings are bonded to hydrogen , or a physiologically acceptable salt of such a compound for the preparation of a pharmaceutical composition for modulating a PDZ domain-containing protein.
  • R 1, R 2 and R 3 are -Hal, especially -Cl, and / or when R 1 is -NO 2, wherein R 2 and R 3 are -H.
  • a pharmaceutical composition of the invention is prepared by mixing the compound in a physiologically effective dose with at least one excipient or carrier.
  • Suitable counterions for ionic compounds are, for example, Na + , K + , Li + or cyclohexylammonium.
  • Suitable solid or liquid galenic preparation forms are for instance granulates, "powders, dragees, tablets, (micro) capsules,"'suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (previous ip, im, sc) or Nebulization (aerosols), transdermal systems, as well as preparations with protracted release of active ingredient, in the preparation of conventional auxiliaries such as carriers, blasting, binding, coating, swelling, lubricants or lubricants, flavoring agents, sweeteners and solubilizers, are used.
  • As adjuvants may be magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol.
  • animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil
  • polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol.
  • Examples of possible indications include cancer, schizophrenia, depression and anxiety, Parkinson's disease, Huntington's disease, Alzheimer's disease, epilepsy, chronic and neuropathic pain, aberrations of hormone-regulated food intake.
  • PDZ domains play an important role in the modulation of proteins associated with these diseases (Dev, KK, Nat Rev. Drug Discov 3: 1047-1056 (2004)).
  • the above compounds bind to the PDZ domain of proteins and are therefore capable of modulating the relevant proteins or the complexes formed in the cell by these proteins, i.e.. to activate or inhibit. For example, it will be advisable to inhibit those proteins which are differentially expressed as being differentially expressed in a disease such as a cancer, e.g. disease-related upregulated or downregulated, have proven.
  • the invention further provides a method for identifying a modulator of a PDZ domain-containing protein, wherein a structural model of a modulator candidate is optionally first compared with a structural model of a reference compound which binds to the PDZ domain and is preselected on overlapping bioisosterer atoms, and wherein the structural model of the optionally preselected modulator candidate is compared with a structural model of the protein or a structural model of a complex of protein and modulator candidate is examined and it is determined whether the modulator candidate binds to the PDZ domain, wherein the Structural model of the protein or the complex derived i) from structural coordinates of the complex with the reference compound, ii) a PDZ-containing fragment of the complex with the reference compound, or a homolog to i) or ii).
  • prospective compounds especially compounds with a molecular weight below 5000 to 1000 or less, as it were "tried” to the structural model of the PDZ domain or the protein. If a binding is detected by the comparison, the prospective compound is selected and may then be subjected to further attempts to develop pharmaceutical compositions.
  • the protein in the complex takes on a special conformation, which does not occur in all previously published structural models of PDZ domains and has a new hydrophobic binding pocket, which can make a decisive contribution to the binding strength of modulator candidate. Therefore, the structural coordinates of the protein of the invention in complex with compound 1 present the protein in a particular small molecule binding conformation of the present invention which is advantageous for the success of the method of the invention.
  • the comparison can thus pattern the structural model of the complex of protein with compound 1 to bring new, unknown test compounds into association with bound compound 1.
  • This method is referred to as ligand-based virtual screening. If bioisosteric atoms of a modulator candidate overlap with the atoms of compound 1 without repulsive overlapping with the protein, the modulator candidate can be identified as a new modulator. If a modulator candidate, in addition to the aforementioned conditions, fills one or more other binding pockets of the protein which are not covered by compound 1, then the modulator candidate can be identified as a new modulator having higher affinity and / or higher specificity.
  • the comparison may thus comprise connecting the structural model of the candidate candidate, after a pre-comparison of the modulator candidate with compound 1, with the structural model of the protein, based on the structural coordinates of the complex according to the invention, optionally with the free binding energy of the bond between modulator candidate and Protein is determined, and at low free binding energy, a high binding probability is detected.
  • the free binding energy can be calculated: a) by summation of the free energies of interatomic contacts between the structural model of the modulator candidate and the structural model of the protein, and / or b) by determining the free binding energy between the force field of the modulator candidate and the Force field of the protein.
  • the invention accordingly also relates to the use of the structural coordinates in the small molecule binding conformation with compound 1 i) of the protein AF6, ii) a fragment of AF6 containing a PDZ domain, or iii) a homolog to i) or ii) for the identification of a modulator a PDZ domain-containing protein, preferably in a screening method of the invention.
  • the invention further comprises a machine-readable storage medium containing machine-readable data which, when read and processed by a data processing system with a suitable program, provides a representation of the structural model of a protein or a complex according to the invention, a computer program with a program code for carrying out a method according to the invention or a use according to the invention, and a
  • Data processing system comprising a computer program according to the invention and a machine-readable storage medium according to the invention.
  • Example 1 Substances according to the invention
  • FIGS. 1A, 1B, 2A, 2B show the novel compounds 1 - 2, 4 - 7, 16 and 21 according to the invention, which bind to the PDZ domain of the protein AF6.
  • FIGS. 1A, 1B, 2A, 2B show the previously known compounds 3, 8, 9-15 and 17-20, which are suitable for the uses according to the invention, since they likewise bind to the PDZ domain of the protein AF ⁇ .
  • FIGS. 3A to 3D show compounds which are not compounds according to the invention because they do not bind to the PDZ domain of the protein AF ⁇ .
  • Binding to the PDZ domain show the following compounds: 1, 7, 9, 6 and 2.
  • Example 2 Substances which can also be used according to the invention
  • Figures 4 and 5 show further compounds useful in the invention that bind to the PDZ domain.
  • the explanations given in Example 1 apply correspondingly to the markings.
  • the compounds in FIG. 2B can be prepared according to Example 3.1 using 2, 4-thiazolidinediones instead of 2, 4-thioxothiazolidines-one.
  • Example 3.3 Synthesis of compounds 1-5 in Fig. IA and connections 26 and 28 in FIG. 3A.
  • the compounds in FIG. 1B can be prepared according to Example 3.2 followed by the following process steps: A 2.0 molar solution of lithium borohydride (2.2 equivalents) in tetrahydrofuran (THF) is added with stirring to a solution of 5-arylidenes-2,4-thiazolidinedionene in pyridine and THF under nitrogen atmosphere at room temperature. The mixture is heated to reflux until the reduction reaction is complete (about 3 to 5 hours). The mixture is then cooled, carefully added to a dilute hydrochloric acid solution in distilled water at 5 ° C and extracted several times with ethyl acetate. The ethyl acetate extracts are combined, washed with water, dried over MgSO 4 and concentrated on a rotary evaporator. The crude product is purified by silica gel flash chromatography, resulting in the final product.
  • THF tetrahydrofuran
  • Compounds 31 and 32 in Figure 3B can be prepared as follows: To a mixture of N-methylrhodanine (0.735 g, 5 mmol) and aryl-aldehyde (5 mmol) in a minimum volume of dichloromethane is potassium fluoride on aluminum (2 g). The solvent is removed under reduced pressure and the remaining solids are irradiated with microwave at 150 ° C. for 10 min. The reaction products are extracted with dichloromethane, filtered through Celite and concentrated. The crude product is purified by silica gel flash chromatography, resulting in the final product.
  • Compound 16 in Figure 2A can be prepared as follows: A mixture of 2,4-thioxothiazolidines-one (0.66 g, 5 mmol), 4 '- (trifluoromethyl) -acetophenone (0.94, 5 mmol), piperidine (0.40 mL , 4 mmol) and THF is irradiated for 10 min at 100 0 C with microwaves. The crude product is purified by silica gel flash chromatography, resulting in the final product.
  • the compound 6 in FIG. 1A can be prepared according to Example 3.7, followed by the further synthesis route according to Example 3.9.
  • Compounds 35-37 in Fig. 3C can be prepared as follows: A mixture of 5- (4- Trifluoromethylbenzylidenes) -4-oxo-2-thiazolidinethionene (10 mmol) in aqueous NaOH (2%, 25 mL) is treated with methyl iodide (Compound 35), isopropyl iodide (Compound 36) or p-methoxybenzyl iodide (Compound 37) (11 mmol each). stirred at room temperature overnight. The crude product is purified by silica gel flash chromatography, resulting in the final product.
  • Trifluoromethylbenzylidene) -4-oxo-2-thiazolidinethione (1 mmol) and 2-dimethylamino-ethylamine or 3-phenylpropylamine (1 mmol) in THF (1.5 mL) is irradiated for 15 min at 120 0 C with microwaves.
  • the crude product is purified by silica gel Fla-sh chromatography, resulting in the final product.
  • a complex of the human protein AF6 with compound 1 of Figure IA was examined by NMR spectroscopy for its 3D structure. Specifically, this was done as follows: The 15N and 15N / 13C isotope-labeled protein of the PDZ domain of AF6 was prepared as previously described [Boisguerin, P. et al., Chem. Biol. 11: 449-459 (2004)]. , For NMR protein backbone assignment, a Sample of 1.3 mM 15N / 13C-labeled PDZ domain in 20 mM phosphate buffer (pH 7.0), 50 mM NaCl, Complete [R] protease inhibitor and 10% (v / v) D2O.
  • NMR spectra were recorded at 300 K on a Bruker DRX600 spectrometer with a Z-gradient inverse triple-resonance probe.
  • the NMR raw data were processed with the software XWIN-NMR and analyzed by Sparky software.
  • the triple-resonance NMR experiments CBCA (CO) NNH / CBCANNH and HA (CO) NNH / HANNH as well as some side-chain selective experiments as in [Wiedemann, U. et al., J. MoI Biol. , 343 (3): 703-18 (2004)].
  • Interproton distances for the 3D structure determination were obtained by recording and evaluating the following NMR experiments: 3D-15N-NOESY-HSQC (80ms) and 3D-13C-NOESY-HMQC (80ms).
  • 3D structural models were calculated using the software Cyana [Guntert P., Mol Biol., 278: 353-78 (2004)].
  • the 20 lowest-energy 3D structural models were analyzed using the software MOLMOL [Koradi R, et al. , J Mol. Graph., 14 (1): 51-5, 29-32 (1996)] and the PROCHECK-NMR software [Laskowski RA, et al. , J Biomol NMR, 8 (4): 477-8 ⁇ (1996)].
  • the protein coordinates of the lowest-energy structural model from the calculation with the software Cyana as well as the protein-ligand-interproton Distances from the NMR experiments were used as input data for computer-assisted docking of the ligand-protein complex.
  • a 2 nanoseconds Molecular Dynamics simulation of the input data in an octahedrally limited water box was performed with the help of the software AMBER 8.0.
  • the final coordinates of the protein-ligand complex are shown in Table 1.
  • Figures 6A, 6B and 6C show the obtained structural models for the complex of Compound 1 and the PDZ domain of AF6.
  • the protein backbone ensemble of the 20 lowest energy structural models in Figure 6A shows a small standard deviation of the coordinates in the secondary structural elements, i. a good quality of the structural model in these regions important for ligand binding.
  • the protein backbone band model of the averaged structure from the 20 lowest energy structures complexed with compound 1 (Figure 6B) is in the same orientation as shown in Figure 6A.
  • Figure 6B The protein backbone band model of the averaged structure from the 20 lowest energy structures complexed with compound 1
  • Figure 6A The protein backbone band model of the averaged structure from the 20 lowest energy structures complexed with compound 1
  • Figure 6B is in the same orientation as shown in Figure 6A.
  • the secondary structural elements folding sheet ß2 and helix ⁇ 2 which are important for the binding of natural peptide ligands, are characterized.
  • FIG. 6C The surface representation of the PDZ domain in complex with compound 1 (FIG. 6C), which is likewise shown in the same orientation as in FIGS. 6A and 6B, shows how in particular the trifluoromethylphenyl radical of compound 1 is transformed into a compound Ties binding pocket of the protein. Many atoms of this residue are almost or completely van der Waals to atoms of the protein, suggesting that no substituents with more than two carbon atoms are allowed at these positions. This result is consistent with the non-binding compounds 29 and 30 in Fig. 3A. By looking at the structural model in FIG.
  • FIG. 8 shows, for a systematic selection of test compounds, which changes in binding affinity and binding site occupancy are experimentally obtained using the method.
  • Each column in Figure 8 shows the amino acid residues of the PDZ Domain of AF6, the backbone amide resonances on addition of the indicated compound in 8 to 10-fold excess ligand in the NMR assay previously described show chemical shift changes.
  • amino acid residues are abbreviated by the internationally common 1-letter code.
  • the numbering of the amino acid residues is identical to the numbering in the protein-ligand complex in Table 1.
  • the chemical shift changes are divided into the 2 categories “large (bold italic font)” and "small. (Normal font)”. From the amino acid residues shown, the binding site of a compound on the protein can be reconstructed by highlighting in detail the backbone amide atoms of these amino acid residues in the 3D protein structure of Table 1 and forming the largest common intersection of all of these atoms on the protein surface.
  • Kd values for the PDZ domains of AF ⁇ and syntrophin are shown in Table 2. Given that the two PDZ domains are low drugability proteins, the Kd value of 101 ⁇ M for compound 1
  • ATOM 31 HDl2 ILE 2 0.539 -5.667 -6.901 1.00 0.00
  • ATOM 38 CA ILE 3 5.204 -5.732 -7.516 1.00 0.00
  • ATOM 112 HD21 LEU 7 -7.223 7.570 2. 078 1.00 0.00
  • ATOM 181 CA ASN 11 11,076 7,481 6,104 1.00 0.00
  • ATOM 182 C ASN 11 -9,560 7,071 5,943 1.00 0.00
  • ATOM 238 HD22 LEU 15 2.297 -4.240 2.494 1.00 0.00
  • ATOM 241 HD12 LEU 15 4.113 -2.433. 0.845 1.00 0.00
  • ATOM 268 HD12 ILE 17 4.613 0.033 5.767 1.00 0.00
  • ATOM 362 CD GLN 25 20.919 -8.988 -0.209 1.00 0.00
  • ATOM 434 CA ILE 30 7.208 -3.174 0.922 1.00 0.00
  • ATOM 442 HB ILE 30 5,579 -1,872 1,174 1.00 0.00
  • ATOM 446 HD12 ILE 30 5.201 0.391 -0.454 1.00 0.00
  • ATOM 453 CA TYR 31 5.820 -6.773 1.012 1.00 0.00
  • ATOM 651 CA GLY 45 10,600 -4,113 -2,949 1.00 0.00
  • ATOM 658 CA ARG 46 11.916 -7.465 -1.351 1.00 0.00
  • ATOM 673 HD3 ARG 46 16.508 -6.477 -1.054 1.00 0.00
  • ATOM 674 HD2 ARG 46 -15.943 -8.015 -1.524 .00 0.00
  • ATOM 702 C ALA 48 -5,586 -9,925 600, 00 0.00
  • ATOM 721 CA GLY 50 -0.022 -10.861 1. 457 1.00 0.00
  • ATOM 740 CA GLN 52.305 -6.576 -2.497 1.00 0.00
  • ATOM 768 HD21 LEU 53 1., 246 1.072 -1.860 1.00 0.00
  • ATOM 834 CA GLY 58 0.351 6.755 -10.376 00 0.00
  • ATOM 841 CA ARG 59 3,493 6,324 -9,836 1.00 0.00 ATOM .842 C ARG 59 4.089 5.377 -8.834 1..00 0.00
  • ATOM 892 HD13 LEU 61 6. 111 6,002 -1 857 00 0.00

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des composés se liant au domaine PDZ de protéines à domaines PDZ, des utilisations de ces composés ainsi que des méthodes de criblage pour l'identification desdits composés.
EP06722837A 2005-05-09 2006-04-28 Modulateurs du domaine pdz Withdrawn EP1893199A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005022182A DE102005022182A1 (de) 2005-05-09 2005-05-09 Modulatoren der PDZ-Domäne
PCT/DE2006/000779 WO2006119736A2 (fr) 2005-05-09 2006-04-28 Modulateurs du domaine pdz

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EP1893199A2 true EP1893199A2 (fr) 2008-03-05

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EP (1) EP1893199A2 (fr)
DE (1) DE102005022182A1 (fr)
WO (1) WO2006119736A2 (fr)

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WO2008148747A2 (fr) * 2007-06-08 2008-12-11 University Of Copenhagen Modulateurs du domaine pdz
JPWO2011105334A1 (ja) * 2010-02-26 2013-06-20 保土谷化学工業株式会社 電荷制御剤およびそれを用いたトナー
WO2012073756A1 (fr) * 2010-11-29 2012-06-07 保土谷化学工業株式会社 Agent de contrôle de charge et toner l'utilisant
CN107382996B (zh) * 2017-06-30 2020-11-06 中国农业大学 一种特异性抑制植物质膜H+-ATPase的化合物及其制备方法和应用
WO2021133037A1 (fr) * 2019-12-26 2021-07-01 연세대학교 산학협력단 Dérivé de pyrrolidine et composition pharmaceutique de prévention ou de traitement de maladies associées à la protéine bêta-amyloïde ou tau contenant ce dernier

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WO1999003974A1 (fr) * 1997-07-15 1999-01-28 The Regents Of The University Of California Compositions et procedes servant a identifier des modulateurs de transducisomes, nouvelle categorie de cibles therapeutiques
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AU1254700A (en) * 1998-11-20 2000-06-13 Mount Sinai Hospital Corporation Peptides that modulate the interaction of b class ephrins and pdz domains
US20040115626A1 (en) * 2000-05-25 2004-06-17 Masahide Goto Human pgc-1 promoter
WO2002007751A1 (fr) * 2000-07-25 2002-01-31 Axcell Biosciences Corporation Identification et isolement de nouveaux polypeptides comportant des domaines pdz et leurs methodes d'utilisation
AU2002252015A1 (en) * 2001-02-16 2002-09-04 Arbor Vita Corporation Pdz domain interactions and lipid rafts
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EP1585541B1 (fr) * 2002-12-20 2007-11-14 Novo Nordisk A/S Compositions pharmaceutiques contenant de l'insuline et des ligands de l'hexamère d'insuline
BRPI0408229A (pt) * 2003-03-11 2006-02-21 Novo Nordisk As preparação farmacêutica, métodos para preparar um ligando de ligação de zinco, para prolongar a ação de uma preparação de insulina estabilizada por ácido e para tratar diabete do tipo 1 ou tipo 2, e, uso de uma preparação
US7141600B2 (en) * 2003-04-15 2006-11-28 The Regents Of The University Of California Small molecule inhibition of a PDZ-domain interaction

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Title
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US20090204336A1 (en) 2009-08-13
DE102005022182A1 (de) 2006-11-16
WO2006119736A2 (fr) 2006-11-16
WO2006119736A3 (fr) 2007-09-20

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