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WO1997045117A1 - Prodrogues du thalidomide et procedes d'utilisation desdites prodrogues comme modificateurs de cellule t - Google Patents

Prodrogues du thalidomide et procedes d'utilisation desdites prodrogues comme modificateurs de cellule t Download PDF

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Publication number
WO1997045117A1
WO1997045117A1 PCT/US1997/009421 US9709421W WO9745117A1 WO 1997045117 A1 WO1997045117 A1 WO 1997045117A1 US 9709421 W US9709421 W US 9709421W WO 9745117 A1 WO9745117 A1 WO 9745117A1
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WO
WIPO (PCT)
Prior art keywords
thalidomide
pro
prodrug
dipeptide
amino acid
Prior art date
Application number
PCT/US1997/009421
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English (en)
Inventor
Robert E. Smith
Original Assignee
Prototek, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Prototek, Inc. filed Critical Prototek, Inc.
Priority to EP97927902A priority Critical patent/EP0914123A4/fr
Priority to CA002256669A priority patent/CA2256669A1/fr
Priority to AU32249/97A priority patent/AU3224997A/en
Publication of WO1997045117A1 publication Critical patent/WO1997045117A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic

Definitions

  • the present invention relates to a new, safe and effective form of thalidomide ( [N-phthalimido]-glutarimide) and methods of using the same. More specifically, the invention relates to prodrugs of thalidomide and prodrugs of certain analogs of thalidomide, which comprise a thalidomide or analog component having bound thereto the dipeptide sequence X-pro, wherein "X" is one of a wide variety of amino acids and "pro” represents the imino acid proline.
  • Thalidomide was first described in 1953 by Ciba and subsequently marketed by Chemic Grunenthal as an anticonvulsant for the treatment of epilepsy. The drug proved ineffective for this purpose; nevertheless it did induce good sleep. It achieved wide use in Europe as a "safe” alternative to barbiturates and later was used as an anti-emetic agent in pregnant women. The compound appeared so nontoxic in rodent models that an LD50 could not be established. In 1961, however, limb defects in babies from mothers using thalidomide during pregnancy were described. Thalidomide proved to be a potent teratogen and was removed from the market due to extreme concerns about the threat of handicapping new generations of people by its teratogenic side effects.
  • thalidomide has also been used for rheumatoid, sarcoidosis, systemic lupus erythematosus, Behcet ' s disease, in acute and chronic graft vs. host disease (GVHD) following bone marrow transplantation and as an immunosuppressant agent in preventing cardiac allograft rejection.
  • GVHD graft vs. host disease
  • the drug has also lately become the object of wide-ranging research for its proposed value in treating a number of AIDS-related conditions, including aphthous ulcers, wasting, tuberculosis, as well as for treating HIV infection itself and the loss of functional CD4 T cells.
  • the present invention provides prodrugs of thalidomide (and prodrugs of certain analogs of thalidomide), which preferably comprise a thalidomide component having bound thereto a dipeptide leaving group.
  • a dipeptide selected according to the invention preferably has the sequence X-pro, wherein "X” is one of a wide variety of amino acids and "pro” represents the imino acid proline.
  • Inventive thalidomide prodrugs are inactive until metabolically altered by, for example, a site-specific enzyme, which activates the thalidomide component by removing the dipeptide therefrom.
  • the present invention provides prodrugs of thalidomide, and methods for making and using the same.
  • Prodrugs of the invention may be administered to a patient, thereby delivering an inactive form of thalidomide which subsequently may be activated in a site-specific manner. Thereby, beneficial drug activity is achieved at a target site without systemic delivery of the active drug.
  • a method for treating a patient comprising providing a composition which comprises a thalidomide prodrug and administering the thalidomide prodrug to the patient.
  • the prodrug preferably comprises a thalidomide component having bound thereto a dipeptide comprising the sequence X-pro; wherein "X" is one of a wide variety of amino acids and "pro” represents the imino acid proline.
  • the composition comprises a thalidomide prodrug and a pharmaceutically acceptable carrier.
  • a composition useful for selectively treating Aphthous ulcers, wasting, tuberculosis, dementia, fevers, fatigue, HIV infection and the loss of functional CD4 T cells comprising a thalidomide component having a dipeptide selected in accordance with the invention bound thereto. Also provided are methods for making these thalidomide prodrugs. It is an object of the present invention to provide a method for delivering the proven beneficial drug thalidomide to a patent in the form of a prodrug made or selected in accordance with the invention, thereby reducing systemic residence of the active drug and, correspondingly, the risk of extremely unsatisfactory side effects.
  • a prodrug of thalidomide including therein a dipeptide leaving group having a proline imino acid in the penultimate location.
  • the present invention provides safe and efficacious compositions comprising derivatives of thalidomide or derivatives of a molecule substantially similar to thalidomide and having functionality substantially similar to thalidomide.
  • the specific types of derivatives contemplated by the present invention are derivatives termed "prodrugs," this term being used herein to refer to an inactive form of a drug that can be enzymatically or physiologically converted to the active form.
  • an inventive thalidomide derivative is a prodrug comprising a thalidomide component having bound thereto a "leaving group" which comprises a dipeptide or oligopeptide that is hydrolized from the thalidomide component by the specific activity of an enzyme.
  • prodrug a drug in a proform
  • endogenous drugs are stored as prodrugs until they are needed.
  • the discovery by Dr. Donald Stiner in the late 1960's that insulin was synthesized and stored within the islet b cells as proinsulin and processed to an active hormone (active drug) by a specific protease was the first example of this phenomenon.
  • the present invention is a novel use of the concept of prodrugs which finds extremely advantageous use in providing site-specific thalidomide activity in a patient.
  • the invention also provides methods for using such thalidomide prodrugs to treat a number of AIDS-related conditions, including aphthous ulcers, wasting, tuberculosis, as well as for treating HIV infection itself and the loss of functional CD4 T cells.
  • thalidomide is intended to refer to thalidomide as well as substantially similar molecules having substantially similar functionality.
  • many drugs and other molecules have non-active sites which may be chemically altered without substantially altering the functionality of active sites thereof.
  • the present invention encompass prodrugs of such thalidomide analogs which insubstantially differ from thalidomide with respect to structure and functionality.
  • the invention relates to the highly site-specific activation of a prodrug to its active form, this activation being restricted to specific cell types where the drug is desired to provide pharmacological activity.
  • prodrug derivatives of thalidomide are provided which comprise a thalidomide component bound to a dipeptide leaving group which may be removed by a hydrolysis reaction catalyzed by an enzyme specific to a particular cell type.
  • the enzyme which activates the thalidomide prodrug is DPP-IV.
  • DPP-IV is very substrate specific in its action (i.e.
  • DPP-IV The biological function of DPP-IV has been well established as a processing protease; its action on proteins is to clip off the 90 degree right or left angle dipeptide to either activate or start the deactivation of the substrate. According to the invention this biochemical mechanism is utilized to activate prodrug forms of thalidomide in situ .
  • Proline the only mammalian imino acid, confers unique restraints on the conformation of a peptide chain, and many biologically important peptide sequences contain conserved site location prolines.
  • the a-nitrogen atom of proline is part of the rigid pyrolidine ring and, at the same time, is covalently bound by means of a secondary amine bond to the preceding amino acid.
  • proline When present inside an a-helix, proline also sterically prevents the amide nitrogen of its C-terminal neighbor from making a hydrogen bond with a carboxyl in the preceding turn of the helix and thus introduces a kink of 20 degrees or more in the ⁇ -helix.
  • proline and hydroxyproline can more readily introduce structural heterogeneity since the amino acid preceding proline can adapt either the stereo isomeric cis or trans conformation with respect to proline.
  • the conformational restrictions imposed by proline motifs in a peptide chain appear to imply important structural or biological functions as can be deduced from their often remarkable high degree of conservation in many proteins and peptides, especially cytokines, growth factors and G-protein-coupled receptors.
  • a remarkable number of cytokines share an X-pro sequence at their aminoterminus (X is one of a wide variety of amino acids) .
  • the N-terminal X-pro sequence may not only contribute to the biological activity, as has been demonstrated for IL-1 and IL-2, but also serve as a structural protection against nonspecific proteolytic degradation analogous to C-terminal amidation, acetylation, or N-terminal cyclization to pyroglutamic acid. It is believed that only the serine protease DPP-IV can cleave the Pro-Z peptide bond (the bond between proline and any amino acid except proline on the carboxy terminus side of proline). The rate of hydrolysis is further affected by whether proline is in the cis or trans state and which amino acid is positioned to the right (Z); a pro-pro bond cannot be cleaved.
  • a X-pro dipeptide is an excellent leaving group for purposes of the present invention because it is selectively removed from the prodrug, thereby activating thalidomide, at specific anatomical locations where the enzyme DPP-IV is present.
  • DPP-IV is very site specific, thus providing an excellent pharmacokinetic profile with respect to thalidomide prodrugs of the present invention.
  • the protease DPP-IV is an intrinsic transmembrane ectopeptidase of the serine class with its catalytic moiety on the extracellular side. It is a sialoglycoprotein; a homodimer anchored by a hydrophobic domain into the plasma membrane of T lymphocytes with a short intracytoplasmic tail of six amino acids. It is preferentially expressed on the cells with CD4* helper/memory (CDx29 ) determinants.
  • DPP-IV is a processing protease with a high substrate specificity toward dipeptides X-Pro at the N-terminal. The enzyme is able to bind and to hydrolyze extracellular cytokine substrates (E.G.
  • DPP-IV is induced in the CL phase following mitogen activation of the T-cell and is essential for the transition from CI to S phase of the cell cycle. In the course of T-cell stimulation in vitro, DPP-IV activity increases by a factor of 4 to 8 with peak activity at day 3 or 4. The expression of cell surface-associated DPP-IV parallels the capacity of the T-cell to produce IL-2. Active-site-specific agents to inhibit the enzyme have shown that membrane bound DPP-IV plays a key role in T-cell mediated immune response.
  • a prodrug made and used according to the invention is prepared so that it is in an inactive state until a leaving group is cleaved from the prodrug, thereby rendering it active.
  • the tissue specific enzyme DPP-IV elicits a localized response such as, for example, a cytokine response that can be therapeutic in HIV infection. While it is not intended that the present invention be limited by statements regarding mechanisms whereby it achieves its advantageous result, such a response is elicited by the activation of an inventive thalidomide prodrug.
  • a thalidomide prodrug is synthesized such that it comprises a thalidomide component bound to the dipeptide sequence X-pro, where "X" is one of a wide variety of amino acids and "pro” represents the imino acid proline.
  • the prodrug includes a dipeptide selected from the group consisting of ala-pro (alanine, proline); lys-pro (lysine, proline) and gly-pro (glycine, proline).
  • these dipeptide derivatives (prodrugs) are uniquely activated by the T-cell ectoenzyme, DPP-IV (dipeptidyl peptidase-IV, a component of CD26) .
  • An inventive prodrug is advantageously used by administering the prodrug to a patient.
  • a composition which comprises an inventive thalidomide prodrug and a pharmaceutically-acceptable carrier, and the composition is administered to a patient, for example, orally or by injection.
  • An inventive prodrug is a safe, novel and effective composition that can be used as a therapeutic product to treat human immune modulated inflammatory conditions and infectious parasitic diseases; in particular HIV.
  • the X-pro dipeptide leaving group of the thalidomide prodrug is conveniently removed via hydrolysis by the ectoenzyme DPP-IV on the plasma membrane of activated monocytes and T-cells, thus releasing the active form of thalidomide proximal to the site of action.
  • the thalidomide is substantially unavailable systemically, is less likely to be rapidly degraded, less sedative, less likely to have teratogenic side effects and could be more selectively targeted to the modulation of various cell types and cytokines, principally TNFa and TNFb, IL-1, IL-2, and IL-6.
  • a commercially available amino-X synthon is treated with a suitable blocking agent to introduce a blocking group that will force subsequent cyclization to a five-membered ring.
  • the blocked amino-X synthon is treated with a substitute phthalic anhydride.
  • the ring is closed using any applicable dehydrating agent under conditions that will not destroy the blocking group. Any required transformations of the substituents(s) on the aromatic ring are carried out be standard procedures taking care not to prematurely remove the blocking group.
  • the blocking group is removed by one of the standard deblocking procedures chosen so as to avoid any deleterious effects to the phthaloyl group or any of its substituents.
  • the peptide is attached either step-wise or as a unit using conventional peptide synthesis methods. Any blocking group on the peptide needed for its introduction is removed.
  • Biotinylated derivatives for determining cell surface binding are produced by: a) suitably modifying the aromatic substituent on the phthaloyl moiety to accept a spacer, b) attaching, by standard peptide synthesis methods, a four to twelve atom spacer containing blocked terminal amino group, c) deblocking the spacer without deblocking the X moiety, d) biotinylating by standard methods, and e) deblocking at X and carrying out whatever further reactions are needed.
  • K562 and HL 60 leukemia cell lines are cultured in RPMI 1640 medium containing 10% fetal bovine serum, 0.5% HEPES, 2% glutamine, and 1% streptomycin/penicillin GIBCO (Grand Island NY) .
  • the cells are grown to a density of 2 X 10 5 cells/ml and subsequently harvested.
  • PBL peripheral blood lymphocytes
  • 20 ml of blood is drawn from healthy controls into vacutainers containing 5 ml of 1% NaFl (Becton/Dickinson) .
  • the blood is diluted with Hanks balanced salt solution (GIBCO) and layered over 50% Ficoll
  • the tubes are sedimented at room temperature for
  • the leukocyte layer is aspirated under sterile conditions after the supernatant has been removed.
  • the leukocytes are washed with 10 ml of Hanks balanced salt solution and placed in RPMI medium with 10% fetal calf serum, HEPES, glutamine, and P/S (GIBCO) at a concentration of 10 cells/ml.
  • Phytohemagluttinin (GIBCO) is then added to a final concentration of 1%.
  • the cells are maintained in culture in a humidified incubator with 5% C0 2 for 48 hours at 37°C and then harvested. The cells are then incubated with various prodrug forms of thalidomide.
  • the ectoenzyme DPP-IV at the surface of T-cells is known to hydrolyze from the N-terminus of peptides residues containing ala-pro.
  • a number of synthetic fluorogenic substrates have been produced which are effectively hydrolyzed by DPP-IV and can be used to verify activity of the enzyme on T lymphocytes and various cell lines used for the in vitro assays.
  • the effectiveness of the T-cell DPP-IV to remove the residue ala-pro from the principal drug moiety, thalidomide is tested as follows.
  • a buffered suspension of the dipeptidyl derivatives of thalidomide is incubated with intact viable cells in HEPES buffered (pH 7.0) isotonic medium at 37°C for periods up to 30 minutes.
  • the cells are then sedimented at 500 X g for 5 min at room temperature.
  • the supernatant is extracted with methylene dichloride to extract free thalidomide.
  • the methylene dichloride extracts are evaporated and taken up in 50 ml of methanol for HPLC analysis.
  • Buffers containing ala-pro-thalidomide are incubated in the presence of T-cells (or other cell lines) with measurable DPP-IV activity.
  • the hydrolysis of the dipeptide derivatives are monitored by analytical HPLC.
  • HPLC separation is done according to the method of Gross and Grutrer (1992), on a TSK gel ODS80TM column (TosoHaas, Montgomeryville (s_p PA) 250 x 4.6 mm i.d.) with a mobile phase of triethylamine phosphate, 0.01 M, pH 3.6 (solvent A) and acetonitrile (solvent B) .
  • Dicarboxylic compounds are rapidly degraded at neutral pH, but not at pH 3.6.
  • Separation is accomplished by three step linear gradients of solvent B; 5% - 15 from 1 to 10 minutes, 15% - 25% from 10 - 20 minutes, and 25% - 55% from 20 to 30 min, all at a flow rate of 1 ml per min.
  • Samples are analyzed on a Millinium 2010 HPLC system (Millipore Corp, Milford, MA) with a 996 photodiode array detector and a Hewlett-Packard 1046A programmable Fluorescence Detector. The identity of compounds is made by comparing the UV absorbance spectra with a library of thalidomide derivatives.
  • DPP-IV activity is monitored with synthetic fluorogenic substrates (Enzyme Systems Products, Dublin, CA) . These substrates contain the Dipeptide ala-pro attached to a leaving group, trifluoromethylcoumarin. Trifluoromethylcoumarin is analyzed by a Fischer 4000 spectrofluorimeter . 2 x 10 cells are incubated with a mM ala-pro-trifluoromethylcoumarin in isotonic HEPES, pH 7.8 buffer for 2 to 30 min.
  • the cells are sedimented at 500 x g for 5 min and the supernatant aspirated for fluorescence analysis.
  • the activity of DPP-IV on T-cells is quantitated and correlated with the findings on the release of free thalidomide derivatives from the dipeptidyl prodrug by DPP-IV containing lymphocytes.
  • monoclonal antibodies to quantitate DPP-IV levels on T lymphocytes correlation is determined between levels of this enzyme with the level of binding and uptake of thalidomide derivatives.
  • Thalidomide derivatives Binding specificity of the prodrug or the released drug Thalidomide derivatives are conjugated with biotin through the R'-amino group of the phthalimide moiety.
  • Biotin conjugates of the thalidomide derivative, once bound to or taken up by the target cell are coupled with added FITC-conjugated avidin and subsequently quantitated by flow cytometry.
  • Quantitation of avidin-FITC is used to determine the binding of the thalidomide derivatives to target cells and analyze CD4 and/or other surface marker fluorescence (i.e. CD26) using PE-coupled monoclonal antibodies.
  • CD4 and/or other surface marker fluorescence i.e. CD26
  • PHA-stimulated PBLs in 100 ml of PBL, pH 7.2 are incubated with 10 ml of avidin-FITC, 10 ml of CD-4-PE (phcoerythrin) and/or CD8-tricolor (Bectin Dickinson) (Dolbeare et al. 1996) .
  • the samples are washed with 5 ml PBL and sedimented at 500 x g for 5 min.
  • the samples are then taken up in 1 ml of PBL for analysis on the flow cytometer.
  • PHA-stimulated PBLs are sedimented at 500 x G for 5 min at room temperature.
  • the supernatant culture medium is poured off and the pellets allowed to drain.
  • the cells are then washed with 5 ml of PBL (0.15 M NaCl, 0.02 M sodium phosphate, pH 7.2), and then sedimented at 500 x g or 5 min at room temperature.
  • the supernatant is poured off and 100 ml of PBL is added, the cells resuspended and incubated with ⁇ o ml each of CD3-phcoerythrin, (Dako, Burlingame, CA) and CD8-phcoerythrin/cyanin 5, (Caltag Laboratories, South San Francisco, CA) for 15 min in reduced light at room temperature.
  • Five ml of PBL is added and the cells resedimented as described above.
  • the cell pellet is drained and resuspended in 1 ml of PBL for flow cytometric analysis.
  • Data acquisition is performed on a FACSort flow cytometer (Becton/Dickinson, San Jose, CA) equipped with a 15mW argon ion laser and a doublet discrimination module using the LYDYD II software (Becton/Dickinson) .
  • the instrument is calibrated prior to data acquisition using unstained PBLs.
  • Fluorescence compensation is performed electronically using CD4-FITC/CD8-PE and CD8-PE/Cy5 stained peripheral blood lymphocytes. For each measurement, at least 20,000 events are collected and information on them stored.
  • the PAINT-A-GATE PRO and the ATTRACTORS software (Becton/Dickinson) are used after converting Consort32 data files into the Apple 7.1 system through the CONSORT FILE EXCHANGE software (Becton/Dickinson) .
  • thalidomide may suppress the production of TNFa by monocytes and that IL-2 production is increased in normal monocytes from individuals treated with thalidomide.
  • the Amersham kit is used for the ELISA testing of human TNFa in HL60 cells.
  • concentrations of the test thalidomide derivatives 0.1 - 100 nM are added to the cell cultures.
  • TNF-a is determined by ELISA assay as recommended by the supplier .
  • IL-2 production in human peripheral blood lymphocytes is be monitored by ELISA assay using a monoclonal anti-IL-2 antibody from DKO. 2 to 4 x 10 6 HPBLs stimulated with PHA for 48 hours are incubated with the monoclonal antibody solution (10 ml) for 20 min in an ELISA assay as described by the supplier.

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Abstract

La présente invention porte sur une nouvelle forme de thalidomide ([N-phtalimido]-glutarimide) sûre et efficace et sur des procédés d'utilisation dudit produit. L'invention concerne plus particulièrement des prodrogues du thalidomide et des prodrogues de certains analogues du thalidomide comprenant un thalidomide ou un composant analogue ayant lié audit thalidomide la séquence X-pro du dipeptide dans laquelle 'X' est un acide de la grande variété amino et 'pro' représente la proline iminoacide.
PCT/US1997/009421 1996-05-29 1997-05-29 Prodrogues du thalidomide et procedes d'utilisation desdites prodrogues comme modificateurs de cellule t WO1997045117A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97927902A EP0914123A4 (fr) 1996-05-29 1997-05-29 Prodrogues du thalidomide et procedes d'utilisation desdites prodrogues comme modificateurs de cellule t
CA002256669A CA2256669A1 (fr) 1996-05-29 1997-05-29 Prodrogues du thalidomide et procedes d'utilisation desdites prodrogues comme modificateurs de cellule t
AU32249/97A AU3224997A (en) 1996-05-29 1997-05-29 Prodrugs of thalidomide and methods for using same as modulators of t-cell function

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1855896P 1996-05-29 1996-05-29
US60/018,558 1996-05-29

Publications (1)

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WO1997045117A1 true WO1997045117A1 (fr) 1997-12-04

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EP (1) EP0914123A4 (fr)
AU (1) AU3224997A (fr)
CA (1) CA2256669A1 (fr)
CZ (1) CZ389398A3 (fr)
WO (1) WO1997045117A1 (fr)

Cited By (28)

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DE19828113A1 (de) * 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
WO2000071571A3 (fr) * 1999-05-14 2001-09-07 Boehringer Sohn Ingelheim Composes anti-tumoraux actives par la proteine fap
US6303661B1 (en) 1996-04-25 2001-10-16 Probiodrug Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals
US6319893B1 (en) 1998-07-31 2001-11-20 Probiodrug Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV
US6500804B2 (en) 2000-03-31 2002-12-31 Probiodrug Ag Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6559314B2 (en) 1999-06-10 2003-05-06 Probiodrug Ag Method for the production of thiazolidin
WO2004098644A1 (fr) * 2003-05-08 2004-11-18 K.U. Leuven Research & Development Promedicaments pouvant etre clives a moyen de cd26
US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US6855689B2 (en) 1999-05-14 2005-02-15 Boehringer Ingelheim Pharmaceuticals, Inc. Enzyme-activated anti-tumor prodrug compounds
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US6949515B2 (en) 1999-08-24 2005-09-27 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7053055B2 (en) 1998-06-24 2006-05-30 Prosidion Ltd. Compounds of unstable DP IV-inhibitors
US7091353B2 (en) * 2000-12-27 2006-08-15 Celgene Corporation Isoindole-imide compounds, compositions, and uses thereof
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
US7320991B2 (en) 2001-02-27 2008-01-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Analogs of thalidomide as potential angiogenesis inhibitors
US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
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US7973057B2 (en) 2003-09-17 2011-07-05 The United States Of America As Represented By The Department Of Health And Human Services Thalidomide analogs
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US6303661B1 (en) 1996-04-25 2001-10-16 Probiodrug Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US7053055B2 (en) 1998-06-24 2006-05-30 Prosidion Ltd. Compounds of unstable DP IV-inhibitors
US7166579B2 (en) 1998-06-24 2007-01-23 Prosidion Limited Prodrugs of DP IV-inhibitors
US7084120B2 (en) 1998-06-24 2006-08-01 Probiodrug Ag Prodrugs of DP IV-inhibitors
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US6319893B1 (en) 1998-07-31 2001-11-20 Probiodrug Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV
US7709502B2 (en) * 1999-05-07 2010-05-04 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines
US8158653B2 (en) * 1999-05-07 2012-04-17 Celgene Corporation Pharmaceutical compositions of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-amino isoindoline
US8288415B2 (en) 1999-05-07 2012-10-16 Celgene Corporation Pharmaceutical compositions of 3-(4-amino-1-oxoisoindolin-2yl)-piperidine-2,6-dione
WO2000071571A3 (fr) * 1999-05-14 2001-09-07 Boehringer Sohn Ingelheim Composes anti-tumoraux actives par la proteine fap
US6613879B1 (en) 1999-05-14 2003-09-02 Boehringer Ingelheim Pharma Kg FAP-activated anti-tumour compounds
US6855689B2 (en) 1999-05-14 2005-02-15 Boehringer Ingelheim Pharmaceuticals, Inc. Enzyme-activated anti-tumor prodrug compounds
US6559314B2 (en) 1999-06-10 2003-05-06 Probiodrug Ag Method for the production of thiazolidin
US6949515B2 (en) 1999-08-24 2005-09-27 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7335645B2 (en) 1999-08-24 2008-02-26 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US6500804B2 (en) 2000-03-31 2002-12-31 Probiodrug Ag Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
US7435420B2 (en) 2000-10-27 2008-10-14 Probiodrug Ag Dipeptidyl peptidase IV inhibitors for the treatment of anxiety
US7091353B2 (en) * 2000-12-27 2006-08-15 Celgene Corporation Isoindole-imide compounds, compositions, and uses thereof
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US7576104B2 (en) * 2000-12-27 2009-08-18 Celgene Corporation Isoindole-imide compounds, compositions, and uses thereof
US8846617B2 (en) 2001-02-14 2014-09-30 Thomas Luger Inflammation inhibiting compounds
US8003608B2 (en) * 2001-02-14 2011-08-23 Thomas Luger Inflammation-inhibiting compounds
US8716315B2 (en) 2001-02-27 2014-05-06 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
US7320991B2 (en) 2001-02-27 2008-01-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Analogs of thalidomide as potential angiogenesis inhibitors
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
US7368576B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US7144856B2 (en) 2001-09-06 2006-12-05 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US7608577B2 (en) 2001-10-12 2009-10-27 Osi Pharmaceuticals, Inc. Peptidyl ketones as inhibitors of DPIV
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
WO2004098644A1 (fr) * 2003-05-08 2004-11-18 K.U. Leuven Research & Development Promedicaments pouvant etre clives a moyen de cd26
EA009727B1 (ru) * 2003-05-08 2008-02-28 Тиботек Фармасьютикалз Лтд. Вич-пролекарства, способные расщепляться под действием cd26
US8236756B2 (en) 2003-05-08 2012-08-07 Consejo Superior de Investigaciones Clentificas (CSIC) Prodrugs cleavable by CD26
WO2004099135A3 (fr) * 2003-05-08 2005-02-17 Tibotec Pharm Ltd Prodrogues de vih clivables par cd26
AU2004236371B2 (en) * 2003-05-08 2009-12-17 Consejo Superior De Investigaciones Cientificas (Csic) Prodrugs cleavable by CD26
US7973057B2 (en) 2003-09-17 2011-07-05 The United States Of America As Represented By The Department Of Health And Human Services Thalidomide analogs
US8546430B2 (en) 2003-09-17 2013-10-01 P2D, Inc. Thalidomide analogs
US8853253B2 (en) 2003-09-17 2014-10-07 P2D, Inc. Thalidomide analogs
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
US9084783B2 (en) 2011-12-02 2015-07-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
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AU3224997A (en) 1998-01-05
CA2256669A1 (fr) 1997-12-04
EP0914123A4 (fr) 2000-10-11
EP0914123A1 (fr) 1999-05-12

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