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  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
  • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
  • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• NON-PEPTIDIC SURROGATES OF THE LDV SEQUENCE AND THEIR USE IN THE TREATMENT OF INFLAMMATION, AUTOIfWUNE DISEASES AND TUMOUR PROGRESSION
• the present invention relates to novel Leu-Asp-VaL (LDV) surrogates, to their preparation and to pharmaceutical compositions comprising them for treatment of several disorders.
• LDV Leu-Asp-VaL
• ECM extracellular matrix
• the integrins are heterodimeric molecules consisting of an alpha ( ⁇ ) and a beta ( ⁇ ) subunits which are non-covalently linked. Eleven ct and six ⁇ subunits have been identified. The pairing of and ⁇ subunits may be cell-type specific and determines ligand specificity.
• the integrins play an important role in linking the ECM with the intercellular actin-containing cytoskeleto : the extracellular portion mediates the binding of adhesive proteins, and the intracellular portion interacts with elements of the cytoskeleton.
• the exit of cells from blood vessels and their ensuing tissue localization depends on receptor-mediated recognition of endothelial cells, their basement membranes and the ECM.
• the ability of various cell types to recognize and attach to components of the ECM may therefore be considered as an essential physiological feature of homeostasis .
• Fibronectin a well characterized ECM-derived cell-adhesive glycoprotein, is present in a variety of ECM-derived cell-adhesive glycoprotein.
• FN is involved in processes that include wound healing, embryonic cell migration and differentiation, cell activation, prolifer ⁇ ation, and adhesion .
• Cell binding to immobilized FN is mediated primarily by surface integrins of the ⁇ i (CD29; very late antigens (VLA) )-subfamily of receptors, including VLA-3, -4 and -5 .
• the minimal tripeptide essential for the cell-adhesive functionality of this domain is the Leu-Asp-Val sequence (LDV; Schemee 1 herein; Humphries et al, 1990), the binding of which is primarily mediated by the o ⁇ i integrin (VLA- 4; Nojima et al, 1990).
• This domain was found to be recognized by integrin receptors of various cell types, such as those on tumor cells and lymphocytes (Guan et al, 1990; Shimizu et al, 1990; Postigo et al, 1991; Roldan et al, 1992).
• VLA-4 integrin was also implicated in the recognition of vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, although this binding site was distinct from that recognized on FN (Elices et al,1990).
• Inhibitors of VLA-4 recognition of FN may thus interfere with cell migration from the circulation to inflammatory sites. Indeed specific interference with VLA-4 activity, was found to inhibit experimental autoimmune encephalomyelitis as well as the elicitation of immune-cell mediated contact sensitivity reaction in mice.
• LDV surrogates are effective inhibitors of cellular or molecular interactions which depend on LDV- sequence recognition. These LDV analogues are herein referred to as "LDV surrogates”.
• the present invention thus relates to compounds of the general formula I
• Xi, X2 and X 4 represent carbon atoms, X s is NH and X 3 is NH or S, and the X x - Xs chain is substituted by one or two oxo groups .
• X., X 3 and X 4 are carbon atoms, 2 is S and X s is NH.
• the invention further relates to methods for the preparation of the LDV surrogates of the invention.
• the LDV surrogates of the invention have various applications related to their inhibition of biological interactions dependent on LDV-sequence recognition, such as integrin-mediated cell functions.
• the invention also relates to pharmaceutical compositions comprising the LDV surrogates for the treatment of several disorders, such as inflammatory disorders, and disorders involving interference with cell-matrix or cell-cell dependent immune processes, such as autoimmune diseases, allergy, graft-versus-host and related reactions, and inhibition of metastasis and tumor progression.
• Fig.l shows specificity of inhibition of T cell adhesion to fibronectin (FN) and laminin (LN) by the following inhibitory compounds: peptides GRGDSP AND EILDVPST, the LDV surrogates AC-16 and EG-45, and the comparison compounds AC- 22 and BL-34.
• Fig.2 shows analysis of inhibition of T cell adhesion to FN by the inhibitory compounds as in Fig.l, at concentrations of 800, 400 and 200 ⁇ g/ml.
• Fig.3 shows dose-dependent inhibition of T cell adhesion to FN by the EILDVPST peptide (white symbols) and the corresponding EG-45 surrogate (black symbols).
• the peptide amino and carboxyl end groups are not involved in recognition by its respective integrin and therefore do not affect its inhibitory activity, as is the case for RGD. It was also further considered that the major contribution of the LDV- containing peptides for binding to their putative integrin- recognition sites on integrins depends on the interaction of the carboxylate moiety of Asp (aspartic acid) inside an hydrophobic pocket in which the side chains of Leu are Val
• LDV surrogates refers to novel compounds of the general formula I herein, and pharmaceutically acceptable salts thereof.
• hydrocarbyl as employed herein includes straight or branched C ⁇ -Cj.2 alkyl and C2-C12 alkenyl or alkynyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, vinyl, allyl and ethynyl; C3-C7 cycloalkyl and cycloalkenyl radicals, such as cyclopropyl, cyclopentyl, cyclohexyl and cyclohexenyl; and C ⁇ -Ci aryl radicals, such as phenyl and naphthyl.
• heterocyclic rings comprising the Xi-Xs chain or part thereof include saturated or unsaturated rings, optionally containing additional 0, S and/or N atoms, and may be optionally substituted by halogen, hydrocarbyl, oxo, thioxo, amino or carboxyl.
• An example is the compound herein designated NG-93, which contains a 13-membered ring.
• X x to X s are NH and one or more are C atoms substituted by oxo groups, such as the compound herein designated AC-16 in which X 3 and X s are -NH, X x is >CH2 and ⁇ a and X 4 are carbonyl groups, of the formula depicted in Scheme 1 herein.
• one or more of Xi to Xs are -NH, one is 0 or S and one or more are C atoms substituted by oxo groups, such as the compound herein designated LB-1, in which X 3 is S, Xs is -NH, X and X2 are >CH 2 and X 4 is carbonyl, and the compound herein designated EG-45, in which X 2 is S, X s is -NH, Xi and X 3 are >CH 2 and X 4 is carbonyl (Scheme 1).
• the atoms of the ⁇ - X s chain together with the C atom adjacent to X 5 form
• a heterocyclic ring such as the compound herein designated NG-93, in which X 3 and X s are -NH, X 2 and ..A. are carbonyl and they form part of a 13-membered heterocyclic ring (Scheme 1).
• the compounds of the invention may be prepared by several procedures.
• LDV analogues wherein X 4 is carbonyl and X 3 is nitrogen e.g. compound AC-16
• L- Asp e.g.,t-butyloxycarbonyl Asp (0-benzyl) wherein amide bonds (i.e., X 5 is -NH and X 2 is carbonyl) are prepared by coupling with carbodiimide as shown in Scheme 2.
• Ester bonds (Xs is oxygen) and thioesters are also prepared by carbodiimide coupling.
• LEV analogues, such as the compound AC-22 are prepared according to the same synthetic scheme using as the starting material protected L- Glu, e.g. t-butyloxycarbonyl Glu-(O-benzyl) .
• Cyclic peptides e.g. NG-93 are prepared by stepwise synthesis on an oxime resin starting from Val attached to the resin and coupling of Asp followed by Leu. The peptide is then cleaved from the resin by an excess of t-Boc ⁇ -amino acid. Removal of the t-butyl protecting groups followed by cyclization (DCC,l-hydroxybenzotriazole) affords the 0-benzyl protected cyclic peptide which is purified by HPLC. Hydrogenolysis of the 0-benzyl group (Pd/C 10%) at atmospheric pressure of H 2 gives the cyclic compound.
• LDV analogues wherein X 3 is sulfur and X s is nitrogen, oxygen or sulfur e.g. compound LB-1
• X 3 is sulfur and X s is nitrogen, oxygen or sulfur
• compound LB-1 are prepared by a Michael addition of 4-methyl-l-pentanethiol to benzyl maleate. The addition takes place preferentially ⁇ - to the ester group. Coupling of the free carboxyl group with isobutyl amine, or alcohol or thiol (dicyclohexyl- carbodiimide, 1-hydroxy-benzotriazole) affords the benzyl- protected analogue. The benzyl group is removed by catalytic hydrogenation and the product, e.g. compound LB-1, is purified, e.g. by recrystallysation.
• the compound EG-45 (Scheme 1) is a LDV peptide surrogate that, in addition to lacking the two terminal groups, also has a peptide bond replaced by a peptide bond surrogate.
• Pseudo-S-CH 2 was chosen since its successful synthesis provides easy access to a new peptide bond replacement for peptides containing an Asp moiety next to the N-terminus.It is expected to be resistant to proteases and its lipophilic character can offer advantages.
• the synthesis of EG-45 was based on the Michael addition of a thiol to a bis-ester of itaconic acid, by the synthetic path outlined in Scheme 3 herein.
• compound BL-34 (Scheme 1) was prepared in a way similar to that used for compound EG-45, with sec-butylamine used for the amide formation in the last step of the synthesis, and was used as a control in the cell adhesion studies.
• LDV analogues wherein X 2 and X 4 are carbonyl and Xx and Xs are oxygen are prepared by Michael addition of malonic acid to diisobutyl maleate followed by decarboxylation.
• X x and Xs are nitrogen, Michael addition of malonic acid to maleic acid diisobutyl amide produces the desired compounds.
• Pharmaceutically acceptable salts of the LDV surrogates of the invention include but are not limited to inorganic salts, such as sodium, potassium, calcium and the like, and organic salts with amines or organic bases, such as piperidine, morpholine and the like.
• the LDV surrogates of the invention can inhibit biological interactions which are dependent on LDV recognition.
• Examples of versatile recognition processes mediated by the LDV pattern encompassed by the present invention include cellular and molecular interactions involving the LDV sequence by the integrin VLA-4. Thus, they can also prevent metastasis.
• the surrogates inhibit lymphocyte interaction with certain antigen- presenting cells and thus inhibit T cell activation and migration, thereby preventing autoimmune diseases.
• the compounds of the invention can be administered to any combination of the compounds of the invention.
• the compounds of the invention can be administered to any combination of the compounds of the invention.
• an effective but essentially non-toxic quantity of the compound is employed in the treatment. Effective amounts may be within the range of 0.01 to 1 mg/kg, preferably 0.5 mg/kg on a regimen in single or more divided daily doses.
• the invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising as active ingredient a surrogate according to : the invention and a pharmaceutically acceptable carrier.
• the compositions may be in the form of tablet, capsule, solution or suspension containing from about 0.7 to 70 mg per unit of dosage of an active compound of the invention or mixtures thereof.
• the compounds may be compounded in conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, etc.
• injections for intravenous administration may be prepared in saline, at a pH level of e.g. 7.4.
• N,N'-Dicyclohexylcarbodiimide (226 mg, 1.1 mmol) was added to a solution containing t-butyloxycarbonyl Asp (0- benzyl) (309 mg, 1.0 mmol) and 1-hydroxybenzotriazole (148
• the crude coupling product was dissolved in CH2CI2 (4 ml) and was cooled to 0°C, trifluoroacetic acid (4 ml) was added and the reaction mixture was allowed to stand 30 min at 0°C and 1 h at room temperature. The solvent and the acid were removed under reduced pressure, thus producing N-tert-butyloxycarbonyl-4-benzyloxy-l-aspartic acid isobutylamide.
• the crude product was pure enough for the next step.
• N,N'-Dicyclohexylcarbodiimide (226, mg, 1.1.mmol) was added to a solution containing isocaproic acid (135 mg, 1.0 mmol) and 1-hydroxybenzotriazole (148 mg, 1.1 mmol) in CH 2 C1 2 / THF 1:1 (v/v) solution (7 ml). The reaction was left overnight at room temperature. Dicyclohexyurea (DCU) was filtered off and washed with dry CH2CI2. The crude product from the previous step was added to that solution along with diisopropyl ethyl amine (260 mg, 2 mmol). The reaction mixture was stirred for 5 h at room temperature.
• DCC N,N'-Dicyclohexylcarbodiimide
• the LEV surrogate AC-22 was prepared by the same procedure as compound AC-16, but using t-butyloxycarbonyl Glu (O-benzyl) instead of the Asp derivative, and was used for comparison with the LDV surrogate compound AC-16.
• Compound BL-34 used for comparison with EG-45, was prepared by the same procedure as compound EG-45 in Example 4, but using sec-butylamine instead of the isobutylamine.
• N- ⁇ -tBoc-Valine was coupled to an oxime resin (DeGrado, W.F. and Kaiser,E.T., 1980, J. Org. Che . 45:1295) using DCC as the coupling reagent.
• oxime resin (2.00g) was added to a solution containing N- ⁇ -tBoc.-valine (1 mmol) and DCC (1 mmol) in methylene chloride (10 ml). The mixture was shaken for 15 h, washed with methylene chloride, DMF, isopropanol and methylene chloride and dried in vacuo.
• VLA-4 integrin plays a major role in cellular interactions with immobilized FN. Indeed, this integrin was shown to participate in various processes, such as lympho-hemopoiesis, bone marrow cell differentiation, VCAM-1 recognition, cell activation, and the binding of FN to several cell types, including tumor cells and lymphocytes (Elices et al,1990; Shimizu et al,1990; Roldan et al,1992). The minimal recognition site on FN for the VLA-4 integrin appears to be restricted to the alternatively spliced V region and is blocked specifically by the LDV-containing peptides (Humphries et al, 1986).
• CD4*T cells were purified from the peripheral blood of healthy human donors. Mononuclear leukocytes were isolated using Ficoll gradients, washed and incubated in RPMI supplemented with 10% FCS and antibiotics in petri dishes at 37°C humidified C0 2 incubator. After 2 h, the non-adherent cells were isolated and applied on nylon-wool columns (1.5 h) . The CD4* T cells were then negatively selected by exposure of these cells to a mixture of anti-CD8, CD19, and CD14 monoclonal antibodies (mAb) conjugated to magnetic-beads (Advanced Magnetics, MA). Cells that did not bind to the beads were exposed to a second round of negative selection. The resulting cell population, which consisted of over 90% CD3* CD4* cells, as determined by FACScan analysis (not shown), was used as the source of human CD4*T cells.
• mAb monoclonal antibodies
• ECM components were first bound to polystirene wells.
• FN or laminin (LN) (Sigma; 1 mg/50 ml medium/well) was added to 96-well flat-bottom microtiter plates (Costar) and incubated for 2 hours. Unbound protein was removed by washing and the remaining binding sites on the plates were blocked by 1% BSA (Sigma) in PBS.
• the T cells were radioactively labeled with ⁇ :L [Cr] (New England Nuclear) and activated with phorbol myristate acetate (PMA;
• T cells were pretreated (30 min at 37°C) with anti-CD29 (anti- ⁇ i chain of VLA integrins; diluted 1/200, Serotec, Oxford, UK), anti- VLA-5, anti-VLA-4, or anti-VLA-6 (diluted 1/400; Telios Pharmaceuticals Research Inc.) mAb.
• anti-CD29 anti- ⁇ i chain of VLA integrins; diluted 1/200, Serotec, Oxford, UK
• anti- VLA-5, anti-VLA-4, or anti-VLA-6 diluted 1/400; Telios Pharmaceuticals Research Inc.
• the RGD peptide GRGDSPK was purchased from Sigma.
• the LDV peptide EILDVPST was synthesized by an Applied Biosystems synthesizer at the Peptide Synthesis Unit, The Weizmann Institute of Science, Rehovot, Israel.
• the sl [Cr]-labeled CD4-T cells (2xl0 5 /well) were then added to the coated microtiter plates and incubated for 30 min at 37°C in a 10% C0 2 humidified incubator.
• the non-adherent cells were then gently removed and the adherent cells were lyzed and collected.
• the percent of cells that were adhered was calculated as follows: [CPM of residual cells in the well/(total CPM of cells added to the well-spontaneous release of sl Cr)x 100]. Results are expressed as the mean percent of T cell binding derived from quadriplicate wells for each experimental group.
• the inhibitory effect of the LDV surrogates on cell adhesion to FN was measured in a way similar to that described for peptide inhibition.
• the freshly isolated and purified human CD4-*"T cells were pretreated with the inhibitory compounds (peptides GRGDSP and EILDVPST, the LDV surrogates AC-16 and EG-45, and comparison compounds AC-22 and BL-34) at a fixed concentration of 600 ⁇ g/ml.
• the cells were then seeded in the FN or LN precoated wells. Percent cell adhesion was calculated thereafter. Values ⁇ SD are shown in Fig. 1 (one experiment representative of 3).
• Fig. 1 The results shown in Fig. 1 indicate that surrogates AC-16 and EG-45 inhibited T cell adhesion to FN.
• the AC-16 mimetic is almost as active as the LDV-containing peptide, while AC-22 is inactive, indicating that the amino and carboxyl terminal groups of the tripeptide LDV are not required for its activity.
• EG-45 was a better inhibitor of T cell adhesion than both AC-16 and the LDV-containing peptide (54, 34, and 46%, respectively).
• Compounds AC-22 and BL-34 did not inhibit T cell adhesion to neither ECM-glycoproteins.
• AC-22 derived from glutamic acid
• AC-22 can be regarded as an LEV surrogate, and its inability to inhibit cell adhesion reflects the situation observed with the LEV-NH 2 peptide (Humphries et al, 1986).
• LEV-NH 2 peptide Humphries et al, 1986.
• compound BL-34 a terminal methyl group from the "amide side” was "shifted" to a position closer to the nitrogen, presumably introducing steric hindrance and interfering with hydrophobic group binding to its receptor pocket. This probably accounts for the poor inhibitory potential of this compound on CD4-T cell adhesion to FN.
• mice with a synthetic EILDVPST peptide inhibited the induction of contact sensitivity, a T cell mediated immune reaction in the dermal micro-environment of mice (Ferguson et al, 1991).
• LDV surrogates may indeed serve as inhibitors of inflammatory reactions.
• Example 8 Inhibition of DTH response in vivo to OX by treatment of mice with LDV surrogates The interference of LDV surrogates with T cell-mediated immune response in vivo was tested.
• a delayed-type hypersensitivity (DTH) reaction experiment was performed in which groups of BALB/c mice (5 mice per group) were sensitized on the shaved abdomen with the skin allergen 4- ethoxymethylene-2-phenyl-oxazolone (OX) (10 ⁇ l of 3% OX in acetone/olive oil) and challenged 5 days later by applying OX to their ears. The increment in ear swelling was recorded 24h
• mice were treated following their OX-priming with intravenous injections of 25 ⁇ g of the LDV-containing peptide or the LDV-mimetic AC-16, or with PBS. The results are shown in Table 2.
• results shown here indicate that daily administration of the LDV-mimetic, but not the LDV-peptide or PBS, inhibited markedly DTH response in vivo.

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