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Definitions

• the present invention relates to cytokine inhibitors. More specifically, the present invention identifies and characterizes several inhibitors of macrophage migration inhibitory factor.
• Macrophage migration inhibitory factor is a potent pro-inflammatory cytokine, critically involved in the pathogenesis of sepsis and other inflammatory disorders (Calandra and Roger, 2003; Riedemann et al., 2003). Sepsis, a lethal systemic inflammatory reaction to infection, kills more than 215,000 people per annum in the US alone. There is currently no anti- inflammatory therapeutic agent that is approved by the FDA, for its clinical management. MIF has been demonstrated to be an important late-acting mediator of systemic inflammation, and inhibiting its activity in vivo attenuates the lethal consequences of endotoxemia and sepsis in rodents (Calandra et al., 2000; Al-Abed et al., 2005).
• MIF exists as a homotrimer (Sugimoto et al., 1995; Sun et al., 1996; Suzuki et al., 1996; Taylor et al., 1999) with the unique ability to catalyze the tautomerization of non-physiological substrates such as D-dopachrome and L-dopachrome methyl ester into their respective indole derivatives (Rosengren et al., 1996).
• N-acetyl-p-benzoquinone imine forms a covalent complex with MIF at its active site (FIG. 1) and is capable of irreversibly inhibiting the adverse biological effect of MIF (Senter et al., 2002).
• the toxicity of NAPQI precludes its use as a viable clinical inhibitor of MIF.
• Rl is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic group, a substituted heterocyclic group, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a hydroxy, an alkoxy, an aryloxy, an oxo, an amino, a halogen, a formyl, an acyl, a carboxy, a carboxyalkyl, a carboxyaryl, an amido, a carbamoyl, a guanidino, a ureido, an amidino, a mercapto. a sulfinyl, a sulfonyl or a sulfonamide, and
• R2, R3, R4 and R5 are independently a halogen, -OH, -SH, -NH 2 , -NO 2 , -OR6, or H, where R6 is a straight or branched C J -C O alkyl.
• the invention is also directed to pharmaceutical compositions comprising any of the above compounds, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
• the present invention is additionally directed to methods of inhibiting macrophage migration inhibitory factor (MIF) activity in a mammal.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to inhibit MIF activity in the mammal.
• MIF macrophage migration inhibitory factor
• the invention is directed to methods of treating or preventing inflammation in a mammal.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to treat or prevent the inflammation in the mammal.
• the present invention is directed to methods of treating a mammal having sepsis, septicemia, and/or endotoxic shock.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to treat the sepsis, septicemia and/or endotoxic shock.
• the invention is further directed to methods of treating a mammal having an autoimmune disease.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to treat the autoimmune disease.
• the present invention is directed to methods of treating a mammal having a tumor, the method comprising administering the above pharmaceutical composition to the mammal in an amount effective to treat the tumor.
• FIG. 1 is a diagram showing a scheme for the rational design of MIF inhibitors.
• FIG. 2 is a chemical formula for compound 10, a di-substituted hydrazone.
• FIG. 3 is a graph of experimental results showing that compound 7 inhibits TNF secretion from LPS-treated macrophages.
• FIG. 4 is a graph of experimental results showing that the hydrazone compound 7 is protective after 24 h late treatment in a CLP model.
• a single injection was composed of 100 ⁇ g of Compound 7 (equivalent to 4 mg/kg) in 200 ⁇ L of 20%
• DMSO 80% saline solution. Additional administrations of compound 7 (bi-daily) were given on days 2 and 3.
• FIG. 7 is a graph of experimental results showing that compound 7 is a protective agent in an animal model of endotoxemia.
• the present invention provides several new compounds that inhibit MIF activity. See Examples.
• Rl is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic group, a substituted heterocyclic group, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a hydroxy, an alkoxy, an aryloxy, an oxo, an amino, a halogen, a formyl, an acyl, a carboxy, a carboxyalkyl, a carboxyaryl, an amido, a carbamoyl, a guanidino, a ureido, an amidino, a mercapto, a sulfinyl, a sulfonyl or a sulfonamide, and
• R2, R3, R4 and R5 are independently a halogen, -OH, -SH, -NH 2 , -NO 2 , -OR6, or H, where R6 is a straight or branched C r C 6 alkyl.
• R2 is fluorine or H. More preferably, only R2 is not an H. Even more preferably, R2 is a halogen and R3, R4 and R5 are all H. Most preferably, R2 is fluorine and R3, R4 and R5 are all H.
• Rl is preferably COOMe, COOEt, COOfBu, COOCH 2 Ph, COOCH 2 PhOMe, COPh, SO 2 Ph, Me, Ph, PhOMe, COO/Bu, Ph, or PhOMe, where Me is CH 3 , Ph is a phenyl, and Bu is a butyl. More preferably, Rl is COO/Bu, Ph, or PhOMe. Even more preferably, the compound is any one of compounds 4 - 9 and 11 - 19 of Tables 1 and 2. Most preferably, the compound is any one of compounds 5, 6, 7, 8, 9, or 19 of Table 1 or 13, 14, 15, or 18 of Table 2. In some aspects, the compound is compound 5 of Table 1. In other aspects, the compound is compound 6 of Table 1.
• the compound is compound 7 of Table 1.
• the compound is compound 8 of Table 1.
• the compound is compound 9 of Table 1.
• the compound can be compound 19 of Table 1.
• the compound can also be compound 13 of Table 2.
• the compound can be compound 14 of Table 2.
• the compound can further be compound 15 of Table 2.
• the compound can additionally be compound 18 of Table 2.
• the invention is also directed to pharmaceutical compositions comprising any of the above compounds, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
• pharmaceutically acceptable it is meant a material that (i) is compatible with the other ingredients of the composition without rendering the composition unsuitable for its intended
• Non-limiting examples of pharmaceutically acceptable carriers include, without limitation, any of the standard pharmaceutical carriers such as phosphate buffered saline solutions, water, emulsions such as oil/water emulsions, microemulsions, and the like.
• compositions can be formulated without undue experimentation for administration to a mammal, including humans, as appropriate for the particular application. Additionally, proper dosages of the compositions can be determined without undue experimentation using standard dose-response protocols.
• compositions designed for oral, lingual, sublingual, buccal and intrabuccal administration can be made without undue experimentation by means well known in the art, for example with an inert diluent or with an edible carrier.
• the compositions may be enclosed in gelatin capsules or compressed into tablets.
• the pharmaceutical compositions of the present invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
• Tablets, pills, capsules, troches and the like may also contain binders, recipients, disintegrating agent, lubricants, sweetening agents, and flavoring agents.
• binders include microcrystalline cellulose, gum tragacanth or gelatin.
• excipients include starch or lactose.
• disintegrating agents include alginic acid, cornstarch and the like.
• lubricants include magnesium stearate or potassium stearate.
• An example of a glidant is colloidal silicon dioxide.
• sweetening agents include sucrose, saccharin and the like.
• flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be pharmaceutically pure and nontoxic in the amounts used.
• the compounds can easily be administered parenterally such as for example, by intravenous, intramuscular, intrathecal or subcutaneous injection.
• Parenteral administration can be accomplished by incorporating the compounds into a solution or suspension.
• solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
• Parenteral formulations may also include antibacterial agents such as for example, benzyl alcohol or methyl parabens, antioxidants such as for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA. Buffers such as acetates, citrates or phosphates and agents for the adjustment of
• 364463.1 tonicity such as sodium chloride or dextrose may also be added.
• the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
• Rectal administration includes administering the compound, in a pharmaceutical composition, into the rectum or large intestine. This can be accomplished using suppositories or enemas.
• Suppository formulations can easily be made by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120 0 C, dissolving the composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
• Transdermal administration includes percutaneous absorption of the composition through the skin.
• Transdermal formulations include patches (such as the well-known nicotine patch), ointments, creams, gels, salves and the like.
• nasal administration includes administering the compound to the mucous membranes of the nasal passage or nasal cavity of the patient.
• Pharmaceutical compositions for nasal administration of the compound include therapeutically effective amounts of the compound prepared by well- known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the compound may also take place using a nasal tampon or nasal sponge.
• the compounds of the invention may be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
• the salts should be both pharmacologically and pharmaceutically acceptable, but non-pharmaceutical Iy acceptable salts may conveniently be used to prepare the free active compound or pharmaceutically acceptable salts thereof.
• Pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicyclic, p-toluenesulfonic, tartaric, citric, methanesulphonic, formic, malonic, succinic, naphthalene-2-suIphonic, and benzenesulphonic.
• pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
• the present invention is additionally directed to methods of inhibiting macrophage migration inhibitory factor (MIF) activity in a mammal.
• the methods comprise administering any of the above pharmaceutical compositions to the mammal in an amount effective to inhibit MIF activity in the mammal.
• MIF macrophage migration inhibitory factor
• the mammal is a human. It is also preferred that the mammal has or is at risk for a condition that comprises an inflammatory cytokine cascade that is at least partially mediated by an MIF.
• a condition that comprises an inflammatory cytokine cascade that is at least partially mediated by an MIF is at least partially mediated by an MIF.
• 364463.1 examples of such conditions include proliferative vascular disease, acute respiratory distress syndrome, cytokine-mediated toxicity, psoriasis, interleukin-2 toxicity, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, inflammatory bowel disease, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vagin
• MIF has been shown to play an important role in autoimmune disease. See, e.g., Cvetjovic et al., 2005.
• the present methods would thus be useful in treatment of autoimmune disease.
• the mammal has or is at risk for an autoimmune disease.
• Non-limiting examples of such autoimmune diseases are multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, graft versus host disease, autoimmune pulmonary inflammation, autoimmune encephalomyelitis, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitus, Crohn's disease, scleroderma, psoriasis, Sjogren's syndrome and autoimmune inflammatory eye disease.
• MIF also is known to promote tumor invasion and metastasis. See, e.g., Sun et al., 2005. The present methods would therefore be useful for treatment of a mammal that has a tumor.
• the invention is also directed to methods of treating or preventing inflammation in a mammal.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to treat or prevent the inflammation in the mammal.
• the mamma! is preferably a human.
• the mammal can have, or be at risk for, a disease involving inflammation, for example proliferative vascular disease, acute respiratory distress syndrome, cytokine-mediated toxicity, psoriasis, interleukin-2 toxicity, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, inflammatory bowel disease, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granul
• the mammal has sepsis, septicemia, and/or endotoxic shock, or is at risk for sepsis, septicemia, and/or endotoxic shock.
• these methods can include the administration of a second anti-inflammatory agent to the mammal.
• second anti-inflammatory agents are NSAIDs, salicylates, COX inhibitors, COX-2 inhibitors, and steroids.
• the mammal has or is at risk for sepsis, septicemia, and/or endotoxic shock and the second treatment is administration of a muscarinic agonist, an adrenomedullin, an adrenomedullin binding protein, a milk fat globule epidermal growth factor VIII, an activated protein C, or an ⁇ 2A-adrenergic antagonist.
• the present invention is also directed to methods of treating a mammal having sepsis, septicemia, and/or endotoxic shock.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to treat the sepsis, septicemia and/or endotoxic shock.
• the invention is further directed to methods of treating a mammal having an autoimmune disease.
• the methods comprise administering the above pharmaceutical composition to the mammal in an amount effective to treat the autoimmune disease.
• autoimmune diseases include multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, graft versus host disease, autoimmune pulmonary inflammation, autoimmune encephalomyelitis,
• Guillain-Barre syndrome autoimmune thyroiditis, insulin dependent diabetes mellitus, Crohn's disease, scleroderma, psoriasis, Sjogren's syndrome and autoimmune inflammatory eye disease.
• the present invention is directed to methods of treating a mammal having a tumor, the method comprising administering the above pharmaceutical composition to the mammal in an amount effective to treat the tumor.
• the pharmaceutical composition can be administered orally.
• the pharmaceutical composition can be administered parenterally.
• Phenolic Hydrazones are Potent Inhibitors of Macrophage Migration Inhibitory Factor Proinflammatory Activity and are Survival-Improving Agents in Sepsis Example Summary
• Phenolic hydrazone carbamates and IC 50 values for inhibition of MIF tautomerase activity.
• the position of the hydroxyl group is a critical feature of the hydrazones in that changing its position from para (IC 50 2.5 ⁇ M) to meta (IC50 150 ⁇ M) resulted in a dramatic loss of its ability to inhibit MIF tautomerase activity. Furthermore, replacing the hydroxyl group with hydrogen, fluoro, amino, methoxy and nitro functionalities afforded hydrazones that were inactive (data not shown). In developing a structure-activity
• hydrazones 3-6 were synthesized from the simple hydrazine, methyl hydrazine, phenyl hydrazine and/?-methoxyphenyl hydrazine.
• the hydrogen substituent of the hydrazone in this compound does not offer any hydrophobic interactions and as a result is a very poor inhibitor of MIF tautomerase activity (Table 1 ).
• This increased binding of the /7-methoxy phenyl hydrazone may be explained by hydrogen bond interactions between the ether oxygen and the known amino acid residues, and the possibility of pi-pi stacking and/or van der Waals interactions between the/j-methoxy phenyl ring and the second hydrophobic region of the MIF active site. It has been reported that the amino acids, Pro-33, Tyr-36, Phe-49, Trp-108, and Phe-1 13, make up the second hydrophobic surface at the rim of the active site of MIF (Dios et al., 2002; Orita et al., 2001).
• Hydrazone 6 is twelve times more potent an inhibitor than L-tryptophan Schiff base 1, so far the most potent inhibitor of MIF described in the literature (Al-Abed et al., 2005; Dios et al., 2002; Cheng and Al-Abed, 2006; Orita et al., 2001; Orita et al., 2002). Recently, it was discovered that mono-fluorination of 2 improved the inhibition of MIF activity (Cheng and Al-Abed, 2006). As a consequence, we synthesized the 3-fluoro, 3-chloro, and 3- bromo-4-hydroxyphenyl derivatives of the more potent hydrazone, namely the p-methoxyphenyl hydrazone (6).
• Compound 10 was a very weak inhibitor of MIF activity, displaying an IC 50 value of 300 ⁇ M. This observation could be accounted for by increased steric hinderance or by the reduced number of hydrogen bonding interactions between the di-substituted hydrazone derivative 10 and the active site of MIF.
• the phenolic hydrazone carbamates 11-15 and 18 were chosen as they displayed key functionalities similar to those of the amino acid Schiff base 1 and 2 (Table 2). These functionalities are the hydroxyl group, phenyl ring and the carboxylate moiety. It has been reported that a secondary hydrogen bond interaction exists between the carboxylate moiety of 2 and lysine-32A of the MIF active site (Dios et al., 2002).
• Intracellular MIF occupies a critical role in mediating the cellular responses to pathways activated by lipopolysaccharide (LPS) endotoxin (Roger et al., 2001 ) and MIF-deficient cells are hyporesponsive to endotoxin (Bozza et al., 1999).
• LPS lipopolysaccharide
• MIF null macrophages can produce 50-60% less T ⁇ F compared to wild type (Al-Abed et al., 2005; Mitchell et al., 2002).
• anti-MIF antibody (10 ⁇ g/ml) inhibits 50% of T ⁇ F release from LPS-treated macrophages (Al-Abed et al., 2005).
• MIF molecular therapeutic target in sepsis
• treatment with anti-MIF antibodies or compound 2 significantly improves survival in septic mice
• serum MIF levels increased to 70% of maximum levels within 24 h post CLP, and peaked at 36 h (Al-Abed et al., 2005).
• phenolic hydrazones were designed and synthesized as non toxic, potent MIF antagonists.
• the structure-activity relationship study suggests that minor changes in functionalization of the hydrazones affect the binding of these compounds to the MIF tautomerase active site.
• compound 7 exhibits the greatest activity of all the compounds tested and is so far the most potent inhibitor of MIF described in the literature (Al-Abed et al., 2005; Dios et al., 2002; Cheng and Al-Abed, 2006; Orita et al., 2001; Orita et al., 2002).
• Compound 7 exhibited a potent anti-inflammatory activity in vitro as demonstrated by suppression of LPS-induced macrophage activation (FIG. 3). Moreover, a relatively low concentration of this small molecule MIF inhibitor improved survival in sepsis when treatment was initiated at 24 hours after the onset of the disease.
• Sepsis is a complex inflammatory disorder and its clinical management is a challenging health issue. Therefore, the finding that compound 7 is effective at 24 hours after the onset of the disorder could be of considerable clinical interest. Additionally, anti-cytokine agents that show efficacy in rodent sepsis models have proved to be valuable therapeutics for a variety of human inflammatory and autoimmune diseases and conditions, such as rheumatoid arthritis and Crohn's ' disease.
• the 13 C spectra were recorded on a GE QE 300 spectrometer at 75 MHz. Chemical shifts are relative to the deuterated solvent peak and are in parts per million (ppm). The coupling constants (J) are measured in Hertz (Hz). The 1 H signals are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multipet) and br s (broad singlet). Low and high resolution mass spectroscopy was carried out at the Mass Spectrometry Facility at the University of Illinois at Urbana-Champaign.
• RAW 267.4 macrophages (10 5 ) were treated with various concentrations of hydrazone 7 (0.01- 100 ⁇ M) 30 min prior to LPS addition. After 16 h of incubation, cell culture supernatants were collected for determination of TNF concentration by ELISA. Data are presented as mean ⁇ S.D. Animal studies. All animal experiments were approved by the Institutional Animal Care and Use Committee of the North Shore-Long Island Jewish Research Institute. Male Balb/C mice, ⁇ 8 weeks old, were subjected to cecal ligation and puncture.
• Spectrophotometric Assay for Enzymatic Activity A fresh stock solution of L-do ⁇ achrome methyl ester (2.4 nM) was generated by oxidation of L-3,4-dihydroxyphenylalanine methyl ester with sodium periodate, producing an orange-colored solution. Activity was determined at room temperature by adding dopachrome methyl ester (0.3 mL) to a cuvette containing 1 ⁇ L of MIF solution (850 ng/ mL) in 50 mM potassium phosphate buffer, pH 6, and measuring the decrease in absorbance from 2 to 20 s at 475 nm spectrophotometrically. The inhibitors were dissolved in
• the cecum was isolated and ligated with a 6-0 silk ligature below the ileocecal valve, and the cecum punctured once with a 22G needle, stool (approximately 1 mm) extruded from the hole, and the cecum replaced in the abdominal cavity.
• the abdomen was closed with two layers of 6-0 Ethilon sutures.
• Antibiotics were administered immediately after CLP (Premaxin 0.5 mg/kg, subcutaneously, in a total volume of 0.5 ml/mouse) and single dose of resuscitative fluid (normal saline solution administered subcutaneously (20 ml/kg-body weight) immediately after CLP surgery (Wang et a!., 1999).
• Example 2 Effect of compound 7 on leukocyte recruitment in response to acute inflammation.
• Air pouches were made according to standard procedures (Garcia-Ramallo et al. s 2002) on Swiss Webster male mice (25-30 g) by injecting sterile air s.c. on day 0 (6 ml) and day 3 (3 ml).
• animals were treated with vehicle (350 ⁇ l of 20% DMSO) or compound 7 (7 mg/kg) either intraperitoneal (i.p.) or gavage (oral) as indicated.
• the animals were challenged by injecting 1 ml 1% carrageenan (in PBS) into the air pouch cavity.
• mice were treated orally with compound 7 at 5.25 and 7 hours, but not 9 hours, before harvesting air pouch cells for quantitation, a significant reduction in
• Example 3 Compound 7 protects mice from fatal endotoxemia. Endotoxemia was induced in Balb/C mice by injection of LPS (16 mg/kg, top or 19 mg/kg, bottom). Mice were treated with either vehicle (350 ⁇ l 20% DMSO) or compound 7 (7 mg/kg) i.p., 2 hrs before and 24 after LPS infusion. Survival of the mice was monitored.

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