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EP1320532A1 - Tetrapyrroles - Google Patents

Tetrapyrroles

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Publication number
EP1320532A1
EP1320532A1 EP01946296A EP01946296A EP1320532A1 EP 1320532 A1 EP1320532 A1 EP 1320532A1 EP 01946296 A EP01946296 A EP 01946296A EP 01946296 A EP01946296 A EP 01946296A EP 1320532 A1 EP1320532 A1 EP 1320532A1
Authority
EP
European Patent Office
Prior art keywords
compound
manganese
complexed
carboxylic acid
alkyl
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Withdrawn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
EP01946296A
Other languages
German (de)
English (en)
Inventor
Irwin Fridovich
Ines Batinic-Haberle
Ivan Spasojevic
James D. Crapo
Brian J. Day
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.)
National Jewish Health
Duke University
Original Assignee
National Jewish Medical and Research Center
Duke University
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Filing date
Publication date
Application filed by National Jewish Medical and Research Center, Duke University filed Critical National Jewish Medical and Research Center
Publication of EP1320532A1 publication Critical patent/EP1320532A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating cellular levels of oxidants and thereby processes in which such oxidants are a participant.
  • the invention also relates to compounds and compositions suitable for use in such methods.
  • Oxidants are produced as part of the normal metabolism of all cells but also are an important component of the pathogenesis of many disease processes.
  • Reactive oxygen species for example, are critical elements of the pathogenesis of diseases of the lung, the cardiovascular system, the gastrointestinal system, the central nervous system, immune system and skeletal muscle.
  • Oxygen free radicals also play a role in modulating the effects of nitric oxide (NO-). In this context, they contribute to the pathogenesis of vascular disorders, inflammatory diseases, autoimmunity, cancer and the aging process.
  • NO- nitric oxide
  • SODs superoxide dismutases
  • CuZn SOD dimeric copper- and zinc-containing enzyme
  • Mn SOD tetrameric manganese-containing SOD
  • EC-SOD tetrameric, glycosylated, copper- and zinc-containing enzyme
  • extracellular fluids and the extracellular matrix contain only small amounts of these enzymes, other extracellular antioxidants are also known to be present, including radical scavengers and inhibitors of lipid peroxidation, such as ascorbic acid and uric acid (Halliwell et al, Arch. Biochem. Biophys. 280:1 (1990)).
  • radical scavengers and inhibitors of lipid peroxidation such as ascorbic acid and uric acid (Halliwell et al, Arch. Biochem. Biophys. 280:1 (1990)).
  • the present invention relates generally to low molecular weight tetrapyrroles suitable for use in modulating intra- and extracellular processes in which partially reduced oxygen species, for example, superoxide radicals, or other oxidants such as hydrogen peroxide, peroxynitrite or lipid peroxide, are participants.
  • partially reduced oxygen species for example, superoxide radicals, or other oxidants such as hydrogen peroxide, peroxynitrite or lipid peroxide
  • the compounds and methods of the invention find application in various physiologic and pathologic processes in which oxidative stress plays a role.
  • the present invention relates to a method of modulating intra- or extracellular levels of oxidants such as superoxide radicals, peroxynitrite, hydroxyl radicals and thiyl radicals. More particularly, the invention relates to a method of modulating normal or pathological processes involving superoxide radicals, nitric oxide or peroxynitrite using low molecular weight antioxidants, and to substituted tetrapyrroles suitable for use in such a method.
  • oxidants such as superoxide radicals, peroxynitrite, hydroxyl radicals and thiyl radicals. More particularly, the invention relates to a method of modulating normal or pathological processes involving superoxide radicals, nitric oxide or peroxynitrite using low molecular weight antioxidants, and to substituted tetrapyrroles suitable for use in such a method.
  • FIG. 2A The schematic structure of biliverdin dimethylester in its "open” keto form, H 3 BVMDE.
  • Fig. 2B The schematic structure of biliverdin dimethylester in its "closed” enol form, H 3 BVMDE.
  • Fig. 2C The dimeric manganese(lJT) complex, ⁇ Mn m BVDME ⁇ 2 .
  • Fig. 2D The Chem-3D presentation of the ⁇ Mn BVDME ⁇ wherein pyrrolic subtituents are omitted for clarity.
  • FIG. 3 The absorbances at 390 nm, 362 nm, and 898 nm are plotted vs concentration of ⁇ Mn m BVDME ⁇ 2 in the methanol in the range 2 x 10 "8 M to 8 x 10 "5 M. The data are obtained in 1 cm and 10 cm spectrophotometric cells, but are presented as though all were obtained in a 10 cm cell.
  • Figure 4 The formation of the ⁇ Mn BVDME ⁇ 2 at 25 °C at 1:1, metal to ligand ratio (20 ⁇ M MnCl 2 and 20 /xMBVDME 3" ) in 90/10 (v/v) methanol/aqueous solution, pH* 7.4, 0.05 M tris buffer.
  • Fig. 5B The ion intensities of the major peaks as a function of cone voltage: circles, protonated ligand H t BVDME "1" ; diamonds, oxidized dimer ⁇ Mn IV BVDME + ,Mn III BVDME ⁇ ; triangles up, cationic dimer ⁇ Mn ra BVDME,Mn ffl XBVDME + ⁇ , includes species that have X as a proton, sodium and potassium; squares, cationic monomer, Mn HBVDME + ; triangles down, oxidized monomer, Mn ⁇ BVDME*.
  • FIGS. 6 A and 6B Freezing point measurements of pure bromoform and bromoform in the presence of 16.8 mM manganese(HI) biliverdin dimethylester and 17.3 mM 4,4 bipyridyl. Three independent measurements were performed, Fig. 6 A, and are averaged for clarity in the shorter period of time in Fig. 6B.
  • Figure 9 Fixed potential chronocoulometric measurements of 0.5 mM ⁇ Mn m BVDME ⁇ 2 and Mn ⁇ t TM-2-PyP 5+ in a 90/10 (v/v) MeOH H 2 O, pH* 7.9 (O.l M NaCl).
  • Figure 10 Cyclic voltammogram of 0.5 mM ⁇ Mn ffl BVDME ⁇ 2 in a 90/10 MeOH/H 2 O, pH* 5.8 and 7.9, scan rate 2 V/s (0.1 M NaCl).
  • FIG. 12 The plot of ⁇ (vrj/vi) -1 ⁇ vs the concentration of ⁇ Mn ra BVDME ⁇ 2 expressed per manganese.
  • the v 0 is the rate of reduction of 10 ⁇ M cytochrome c by O 2 ⁇
  • the v; is the rate of reduction of cytochome c inhibited by the porphyrin catalyst in the presence of 0.1 mM EDTA in 0.05 M tris buffer at pH 7.8, 40 ⁇ M xanthine, ⁇ 2 nM xanthine oxidase at 25 °C.
  • the total volume of the assay solution is 3 mL.
  • FIG. 13 Growth curves of SOD-proficient AB1157 (circles) and SOD- deficient E. coli JI132 in the presence (13 ⁇ M) (diamonds) and absence of ⁇ Mn m BVDME ⁇ 2 (triangle down) in minimal medium (five amino acids) under aerobic conditions, pH 7.8.
  • the 20 mM ethanolic/albumin solution of compound was diluted into the medium.
  • the growth of SOD-deficient E. coli was followed in the presence of 0.15% ethanol only (squares).
  • FIG. 14 Structure of manganese (UI) bilirubin ditaurate.
  • the present invention relates to methods of protecting against the deleterious effects of oxidants, particularly, superoxide radicals, and peroxynitrite, and to methods of preventing and treating diseases and disorders that involve or result from oxidant stress.
  • the invention also relates to methods of modulating biological processes involving oxidants, including superoxide radicals, nitric oxide and peroxynitrite.
  • the invention further relates to compounds and compositions, including low molecular weight antioxidants (eg mimetics of scavengers of reactive oxygen species, including mimetics of SODs and catalases) and formulations thereof, suitable for use in such methods.
  • Mimetics of scavengers of reactive oxygen species appropriate for use in the present methods include substituted tetrapyrroles, or pharmaceutically acceptable salts thereof.
  • the invention includes both metal-free and metal-bound tetrapyrroles, preferably those where the metal ion allows formation of a dimeric cyclic structure.
  • Manganese derivatives are preferred, however, metals other than manganese can be used, for example iron.
  • the five-coordination of the manganese in a dimeric environment increases the specificity of the metal site for the O ' since NO' and H 2 O 2 as well as other ligand binding is restricted. For that same reason the otherwise facile axial ligation of iron metal centers is avoided.
  • Co(lTI/II), Zn(IT), Cu(I/TI) and Ni(U) can also be used as the metal center in tetrapyrrole complexes.
  • the mimetics of the present invention are shown in Figure 1 and include pharmaceutically acceptable salts thereof and dimeric forms thereof (see, for example, Fig. 2C).
  • the mimetics of the present invention can be of Formula I, which depicts derivatives of biliverdin in keto form, or can be of Formula II, which depicts derivatives of formylbiliverdin (Fuhrhop et al, Liebigs, Ann. Chem. 1450-1466 (1974)).
  • Biliverdin is formally derived from protoporphyrin-IX by oxi dative removal of one ⁇ -carbon linkage (see Fig. 1).
  • the present invention includes all related compounds that have one or more of the biliverdin groups substituted, including mesoporphyrin IX (vinyl groups reduced to ethyl), hematoporphyrin IX ( vinyl groups substituted by ⁇ -hydroxyethyls ), deuteroporphyrin IX (no substituent on 2 and 4 beta positions), octaethylbiliverdin (all beta substituents are ethyl groups), etioporphyrin (one ethyl and one methyl group on each pyrrolic unit). (See Table 1 of Fig. 1.)
  • the invention also includes derivatives of bilirubins that are the reduced form of the compounds of Formulas I and ⁇ .
  • the invention further includes the derivatives of the mimetics disclosed in Application No. 08/663,028, Application No. 09/296,615 and Application No. 09/184,982 that can undergo oxidative cleavage with ascorbic acid/O system followed by KOH and BF 3 /MeOH treatment (Bonnet et al, J. Chem. Soc. Chem. Commun. 237-238 (1970)) (where no meso substituents are present).
  • cleavage can be accomplished by treating the porphyrins with thallium (IV) and cerium( ⁇ V) salts (Evans et al, J. Chem. Soc. Perkin. Trans. 768-773 (1978)).
  • Ri through R 8 are, independently, -H, alkyl, 2-hydroxyalkyl, methoxyalkyl, halogen, nitro, cyano, trialkylammonium, formyl, amide of carboxylic acid, alkyl ester of carboxylic acid, carboxylic acid, glucuronyl or glyceryl ester of carboxylic acid, 1,2-dihydroxyalkyl, acetyl, vinyl, glycosyl or, taurate, and ⁇ , ⁇ and ⁇ are, independently, -H, acetyl, glycyl, benzoate, phenylsulfonate, 2-, or 3-, or 4-N-alkyl-pyridyl, nitrophenyl, halophenyl, methoxyalkyl, halogen, nitro, cyano, trialkylammonium, formyl, amide of carboxylic acid.
  • Ri through R 8 are, independently, -H, C ⁇ -C 5 alkyl, 2-hydroxy -Cs alkyl, C ⁇ Csal yl ester of C ⁇ -C 5 carboxylic acid, -Cscarboxylic acid, glucuronyl or glyceryl ester of Ci-C 5 carboxylic acid, 1,2-dihydroxy -C 5 alkyl, acetyl, vinyl, glycosyl, taurate, chloro, fluoro, bromo, nitro, cyano, trimethylammonium, or formyl, and ⁇ , ⁇ and ⁇ are, independently, -H, acetyl, glycyl, benzoato, phenylsulfonato, 2-, 3- or 4-N-C ⁇ -C 5 alkyl-pyridyl, nitrophenyl, bromo-, chloro- or fluorophenyl or 2-, 3- or 4-N-C ⁇ -C 5 alkylsul
  • Fig. 1 Specific examples of mimetics of the invention are shown in Fig. 1, with reference to Formulas I and U and to the R 1 -R.8 and ⁇ , ⁇ and ⁇ substituents shown in Table 1 in the context of Compound I', and in Figure 2.
  • the compound of Fig. 2C is a particularly preferred compound.
  • the compound of Fig. 2C has a specific activity of 10,700 units/mg, about three times as high as that of the enzyme itself.
  • the specific nature of the particular dimeric structure is that it allows the stabilization of the +4 metal oxidation state. This is achieved through the fifth coordination of each manganese of one biliverdin subunit to the enolic oxygen of the other subunit.
  • the compound is stable in the presence of 900-fold excess of EDTA at pH 7.8, thus would resist biological chelators.
  • the compound showed significant protection of SOD-deficient E. coli when growing under aerobic conditions. This bacterial model has been previously proven to predict the potency of the compounds in rodents model of diseases.
  • the manganese biliverdin dimethyl ester has previously been reported by Fuhrhop (Liebigs. Ann. Chem. 1131 (1975)).
  • Fuhrhop Liebigs. Ann. Chem. 1131 (1975)
  • a monomeric, phlorin- type (porphyrin-type) of structure was suggested where enolic proton was hydrogen-bonded to the keto oxygen. That structure would allow the existence only of the Mn(HJ)/Mn(II) redox, which, due to the electron-donating groups on the pyrrole groups of the biliverdin would be too negative in potential to allow any significant SOD-like activity.
  • Mn +2 oxidation state was suggested as a resting state, whereas the actual valence is Mn +3.
  • Mimetics preferred for use in the present methods can be selected by assaying for SOD or catalase activity. Mimetics can also be screened for their ability to scavenge ONOO " (as determined by the method of Szabo et al, FEBS Lett. 381:82 (1996)).
  • SOD activity can be monitored in the presence and absence of EDTA using the method of McCord and Fridovich (J. Biol. Chem. 244:6049 (1969)).
  • the efficacy of a mimetic can also be determined by measuring the effect of the mimetic on the aerobic growth of a SOD null E. coli strain versus a parent strain.
  • parental E. coli (AB1157) and SOD null E. coli. JI132
  • M9 medium containing 0.2% casamino acids and 0.2% glucose at pH 7.0 and 37°C
  • growth can be monitored in terms of turbidity followed at 700 nm.
  • This assay can be made more selective for SOD mimetics by omitting the branched chain, aromatic and sulphur-containing amino acids from the medium (glucose minimal medium (M9), plus 5 essential amino acids).
  • Efficacy of active mimetics can also be assessed by determining their ability to protect mammalian cells against methylviologen (paraquat)-induced toxicity. Specifically, rat L2 cells grown as described below and seeded into 24 well dishes can be pre-incubated with various concentrations of the SOD mimetic and then incubated with a concentration of methylviologen previously shown to produce an LC75 in control L2 cells. Efficacy of the mimetic can be correlated with a decrease in the methylviologen-induced LDH release (St. Clair et al, FEBS Lett. 293:199 (1991)).
  • mice can be randomized into 4 groups of 8 mice each to form a standard 2X2 contingency statistical model. Animals can be treated with either paraquat (40 mg/kg, ip) or saline and treated with SOD mimetic or vehicle control. Lung injury can be assessed 48 hours after paraquat treatment by analysis of bronchoalveolar lavage fluid (BALF) damage parameters (LDH, protein and% PMN) as previously described (Hampson et al, Tox. Appl. Pharm. 98:206 (1989); Day et al, J. Pharm. Methods 24:1 (1990)). Lungs from 2 mice of each group can be instillation-fixed with 4% paraformaldehyde and processed for histopathology at the light microscopic level.
  • BALF bronchoalveolar lavage fluid
  • Catalase activity can be monitored by measuring absorbance at 240nm in the presence of hydrogen peroxide (see Beers and Sizer, J. Biol. Chem. 195:133 (1952)) or by measuring oxygen evolution with a Clark oxygen electrode (Del Rio et al, Anal. Biochem. 80:409 (1977)).
  • T BARS thiobarbituric acid reactive species
  • Active mimetics can be tested for toxicity in mammalian cell culture by measuring lactate dehydrogenase (LDH) release.
  • LDH lactate dehydrogenase
  • rat L2 cells a lung Type II like cell (Kaighn and Douglas, J. Cell Biol. 59:160a (1973)
  • Ham's F-12 medium with 10% fetal calf serum supplement at pH 7.4 and 37°C
  • cells can be seeded at equal densities in 24 well culture dishes and grown to approximately 90% confluence
  • SOD mimetics can be added to the cells over a broad range of concentrations (eg micromolar doses in minimal essential medium (MEM)) and incubated for 24 hours.
  • MEM minimal essential medium
  • Toxicity can be assessed by morphology and by measuring the release of the cytosolic injury marker, LDH (eg on a thermokinetic plate reader), as described by Day et al (J. Pharmacol. Exp. Ther. 275:1227 (1995); oxidation of NADH is measured at 340 nm).
  • LDH cytosolic injury marker
  • the mimetics of the present invention are suitable for use in a variety of methods.
  • the compounds of Formulas I and U, particularly the dimeric metal bound forms thereof are characterized by the ability to inhibit lipid peroxidation. Accordingly, these compounds are preferred for use in the treatment of diseases or disorders associated with elevated levels of lipid peroxidation.
  • the compounds are further preferred for use in the treatment of diseases or disorders mediated by oxidative stress. Inflammatory diseases are examples, including asthma, inflammatory bowel disease, diabetes, arthritis and vasculitis.
  • the compounds of the invention (advantageously, dimeric metal bound forms thereof) can also be used in methods designed to regulate NO- levels by targeting the above-described porphinoids to strategic locations.
  • NO- is an intercellular signal and, as such, NO- must traverse the extracellular matrix to exert its effects. NO-, however, is highly sensitive to inactivation mediated by O " present in the extracellular spaces.
  • the substituted tetrapyrroles of the invention can increase bioavalability of NO ' by preventing its degradation by O 2 " .
  • the mimetics of the invention can also be used as catalytic scavengers of reactive oxygen species to protect against ischemia reperfusion injuries associated with myocardial infarction, coronary bypass surgery, stroke, acute head trauma, organ reperfusion following transplantation, bowel ischemia, hemorrhagic shock, pulmonary infarction, surgical occlusion of blood flow, and soft tissue injury.
  • the mimetics can further be used to protect against skeletal muscle reperfusion injuries.
  • the mimetics (particularly, dimeric metal bound forms) can also be used to protect against damage to the eye due to sunlight (and to the skin) as well as glaucoma, cataract and macular degeneration of the eye.
  • the mimetics can also be used to treat burns and skin diseases, such as dermatitis, psoriasis and other inflammatory skin diseases. Diseases of the bone are also amenable to treatment with the mimetics. Further, connective tissue disorders associated with defects in collagen synthesis or degradation can be expected to be susceptible to treatment with the present mimetics (particularly, dimeric metal bound forms), as should the generalized deficits of aging. Liver cirrhosis and renal diseases (including glomerular nephritis, acute tubular necrosis, nephroderosis and dialysis induced complications) are also amenable to treatment with the present mimetics (particularly, dimeric metal bond forms thereof).
  • the mimetics of the invention can also be used as catalytic scavengers of reactive oxygen species to increase the very limited storage viability of transplanted hearts, livers, lungs, kidneys, skin and other organs and tissues.
  • the invention also provides methods of inhibiting damage due to autoxidation of substances resulting in the formation of O 2 " including food products, pharmaceuticals, stored blood, etc.
  • the mimetics of the invention are added to food products, pharmaceuticals, stored blood and the like, in an amount sufficient to inhibit or prevent oxidation damage and thereby to inhibit or prevent the degradation associated with the autoxidation reactions. (For other uses of the mimetics of the invention, see USP 5,227,405).
  • the amount of mimetic to be used in a particular treatment or to be associated with a particular substance can be determined by one skilled in the art.
  • the mimetics (particularly, dimeric metal bound forms) of the invention can also be used to scavenge peroxynitrite as a negatively charged peroxynitrite anion can compete with negatively charged enolate for the 5 th coordination site of the manganese.
  • diseases/disorders appropriate for treatment using the mimetics of the present invention include diseases of the cardiovascular system (including cardiomyopathy, ischemia and atherosclerotic coronary vascular disease), central nervous system (including AIDS dementia, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease and Huntington's disease) and diseases of the musculature (including diaphramatic diseases (eg respiratory fatigue in chronic obstructive pulmonary disease, cardiac fatigue of congestive heart failure, muscle weakness syndromes associated with myopathies, ALS and multiple sclerosis).
  • cardiovascular system including cardiomyopathy, ischemia and atherosclerotic coronary vascular disease
  • central nervous system including AIDS dementia, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease and Huntington's disease
  • diseases of the musculature including diaphramatic diseases (eg respiratory fatigue in chronic obstructive pulmonary disease, cardiac fatigue of congestive heart failure, muscle weakness syndromes associated with myopathies, ALS and multiple
  • NMD A glutamate receptor
  • NO- oxygen free radicals
  • NMDA-toxicity Well-established neuronal cortical culture models of NMDA-toxicity have been developed and used as the basis for drug development. In these same systems, the mimetics of the present invention inhibit NMDA-induced injury.
  • O 2 ⁇ radicals are an obligate step in the intracellular events culminating in excitotoxic death of cortical neurons and further demonstrate that the mimetics of the invention can be used to scavenge O " radicals and thereby serve as protectants against excitotoxic injury.
  • the present invention also relates to methods of treating AIDS.
  • the Nf Kappa B promoter is used by the HTV virus for replication. This promoter is redox sensitive, therefore, an oxidant can regulate this process. This has been shown previously for two metalloporphyrins distinct from those of the present invention (Song et al, Antiviral Chem. and Chemother. 8:85 (1997)).
  • the invention also relates to methods of treating systemic hypertension, atherosclerosis, edema, septic shock, pulmonary hypertension, including primary pulmonary hypertension, impotence, infertility, endometriosis, premature uterine contractions, microbial infections, gout, cancer and in the treatment of Type I or Type II diabetes mellitus.
  • the mimetics of the invention can be used to prevent injury to pancreatic islet cells and therefore prevent or delay onset of symptoms of diabetes mellitus.
  • the mimetics of the invention can be used to ameliorate inflammatory or oxidative injury to the pancreas and in the prevention and treatment of pancreatitis.
  • the mimetics of the invention can be used to ameliorate the toxic effects associated with endotoxin, for example, by preserving vascular tone and preventing multi-organ system damage.
  • inflammations are amenable to treatment using the present mimetics (particularly, dimeric metal bound forms) (particularly the inflammatory based disorders of emphysema, asthma, ARDS including oxygen toxicity, pneumonia (especially AIDS-related pneumonia), cystic fibrosis, chronic sinusitis, arthritis and autoimmune diseases (such as lupus or rheumatoid arthritis)).
  • Pulmonary fibrosis and inflammatory reactions of muscles, tendons and ligaments can be treated using the present mimetics (particularly, dimeric metal bound forms thereof).
  • EC-SOD is localized in the interstitial spaces surrounding airways and vasculature smooth muscle cells.
  • EC-SOD and O ⁇ mediate the antiinflammatory - proinflammatory balance in the alveolar septum.
  • NO- released by alveolar septal cells acts to suppress inflammation unless it reacts with O 2 " to form ONOO".
  • O 2 ⁇ By scavenging O 2 ⁇ , EC-SOD tips the balance in the alveolar septum against inflammation.
  • Mimetics described herein can be used to protect against destruction caused by hyperoxia.
  • the invention further relates to methods of treating memory disorders. It is believed that nitric oxide is a neurotransmitter involved in long-term memory potentiation. Using an EC-SOD knock-out mouse model (Carlsson et al, Proc. Natl. Acad. Sci. USA 92:6264 (1995)), it has been shown that learning impairment correlates with reduced superoxide scavenging in extracellular spaces of the brain. Reduced scavenging results in higher extracellular O 2 " levels. O 2 " is believed to react with nitric oxide thereby preventing or inhibiting nitric oxide-mediated neurotransmission and thus long-term memory potentiation.
  • the mimetics of the invention particularly, dimeric metal bound forms, can be used to treat dementias and memory/learning disorders.
  • compositions suitable for use in the present methods can be formulated into pharmaceutical compositions suitable for use in the present methods.
  • Such compositions include the active agent (mimetic) together with a pharmaceutically acceptable carrier, excipient or diluent and other additives as appropriate (such as solubilizing agents (e.g., glycerol, polyethylene glycol, and dimethylsulf oxide)).
  • solubilizing agents e.g., glycerol, polyethylene glycol, and dimethylsulf oxide
  • a liposome-based composition can also be used.
  • the composition can be present in dosage unit form for example, tablets, capsules or suppositories. Enteric coated tablets and pills, for example, can be used.
  • the composition can also be in the form of a sterile solution suitable for injection or nebulization.
  • Compositions can also be in a form suitable for opthalmic use.
  • compositions formulated for topical administration such compositions taking the form, for example, of a lotion, cream, gel or ointment.
  • concentration of active agent to be included in the composition can be selected based on the nature of the agent, the dosage regimen and the result sought.
  • the dosage of the composition of the invention to be administered can be determined without undue experimentation and will be dependent upon various factors including the nature of the active agent (including whether metal bound or metal free), the route of administration, the patient, and the result sought to be achieved.
  • a suitable dosage of mimetic to be administered IV or topically can be expected to be in the range of about 0.01 to 50 mg/kg/day, preferably, 0.1 to 10 mg/kg/day.
  • For aerosol administration it is expected that doses will be in the range of 0.001 to 5.0 mg/kg/day, preferably, 0.01 to 1 mg/kg/day. Suitable doses of mimetics will vary, for example, with the mimetic and with the result sought.
  • Biliverdin IX dimethylester H 3 BVDME
  • bilirubin IX H 4 BR
  • bilirubin IX dimethylester H 4 BRDME
  • the HCl, KCl, KNO 3 , EDTA, glucose, phosphate salts, inorganic salts and KOH were from Mallinckrodt, and casamino acids were from Difco.
  • the volumetric standards, 1.0 M and 0.10 M NaOH and lithium hydroxide (anhydrous) were from Fisher Scientific.
  • the 2-methyl-2-propanol (t-BuOH, 99.5+ %), albumin from bovine serum, Pipes disodium salt monohydrate (1,4- piperazinebis(ethanesulfonic acid)), succinic acid and xanthine were purchased from Sigma.
  • Deuterium oxide D 2 O, 99.9% was from Cambridge Isotope Laboratories.
  • Cytochrome c from horse heart (# 30 396), biliverdin IX dihydrochloride (H 3 BVDME x 2HC1), (-80%), 4,4-bipyridyl (99%+), and V.N ' - bis(salicylidene)ethylenediamine (H 2 salen) (99+%) were from Fluka.
  • Xanthine oxidase was prepared by R. D. Wiley and was supplied by K. V. Rajagopalan ((Waud et al, Arch. Biochem. Biophys. 19:695 (1975)). Catalase was from Boehringer. Ammonium oxalate was from J. T. Baker.
  • Ultrapure argon was from National Welders Supply Co, and nitric oxide was from Matheson Gas products.
  • Tris (ultra pure) was from ICN Biomedicals, Inc, NONOate NOC-9 was from CalBiochem and phosphate buffered-saline (PBS buffer) from Life Technologies.
  • Lithium hydrogensuccinate was prepared by neutralizing 1M methanolic solution of succinic acid with 0.5 molar equivalent of LiOH in methanolic solution.
  • Biliverdin and bilirubin 1 mM aqueous stock solutions, pH -10 were used throughout work. Elemental analyses were made by Atlantic Microlab, Inc. Norcross, GA.
  • Biliverdin IX Dimethylester The spectral properties of the biliverdin dimethylester ligand, the protonated keto and enol forms of which (Gray et al J. Chem. Soc. 2264 (1961); Bonnet et al, J. Chem. Soc. Chem. Commun. 238 (1970); Nichol et al, Biochim. Biophys. Acta 177:599 (1969); O'Carra et al, J. Chromatog. 50:458 (1970); Chae et al, J. Am. Chem. Soc. 97:4176 (1975)), H 3 BVDME are shown in Figs.
  • Mn ⁇ PPCl and Mn ⁇ SPPNas obtained from Mid-Century Chemicals (Chicago, .IL), and Mn ffl OEPCl from Aldrich were used as received.
  • Mn m TM(E)-2(4)-PyPCl 5 and Mn ⁇ OBTM-4-PyPCl 4 were prepared as described previously (Batinic-Haberle et al, Inorg. Chem. 38:4011 (1999), Batinic-Haberle et al, J. Biol. Chem. 273:24521 (1998), Batinic-Haberle et al, Arch. Biochem. Biophys. 343:225-233 (1997)).
  • Manganese(III) Biliverdin IX Dimethylester [Mn ⁇ I BVDME ⁇ 2 .
  • the complex was prepared by the modification of the literature methods available for the synthesis of similar compounds (Fuhrhop et al, Liebigs. Ann. Chem. 1131 (1975), Bonnett et a, J. Chem. Soc. Perkin Trans I, 322 (1981)). Accordingly, 50 mg of the recrystallized biliverdin dimethylester was dissolved in a small volume of chloroform and 150 mL of methanol was added. The mixture was heated to - 60 °C followed by the addition of 15-fold excess of manganese(U) acetate (0.3 g in 10 mL methanol).
  • Electrospray Mass Spectrometry Electrospray Mass Spectrometry. ESMS measurements were performed on a Micromass-Quattro LC triple-quadrupole mass spectrometer equipped with a pneumatically assisted electrostatic ion source operating at atmospheric pressure. The 600 ⁇ M, 60 ⁇ M and 6 ⁇ M methanol solutions of BVDME 3" and 1 /2 ⁇ Mn m BVDME ⁇ 2 solutions were introduced by loop injection into the methanol stream. The mass spectra were acquired in continuum mode, scanning from m z 600 to 3000 at different cone voltages in the range 30 V - 180 V. Freezing-Point Depression.
  • Magnetic Susceptibility in Solution Magnetic susceptibilities were determined by the Evans method (Evans, J. Chem. Soc. 2003 (1959)) using 400 MHz Varian NMR spectrometer. Typically - 2 mg of the compound, dissolved in 0.4 mL D 2 O or CD 3 OD containing 0.01 M t-BuOH, was placed in a NMR tube along with a capillary that contained the same solvent mixture.
  • Magnetic Susceptibility in Solid State Magnetic susceptibility of the solid ⁇ Mn BVDME ⁇ 2 was measured on a Faraday balance (Senftle et al, Rev. Sci. Instrum. 29:439 (1958), Thorpe et al, Rev. Sci. Instrum. 30:1006 (1959), Sullivan et al, J. Chem. Educ. 48:345 (1971), Thorpe et al, Coal Geology 36:243 (1998)) automated to record apparent mass changes at programmed temperature and magnetic field intervals. The 5 mg samples were suspended on a Cahn electrobalance with He gas as the heat transfer medium.
  • Electrochemistry of the Manganese(III) Biliverdin Dimethylester Measurements were made using a CH Instruments model 600 voltammetric analyzer as described previously(Batinic-Haberle et al, Inorg. Chem. 38:4011 (1999)).
  • the cyclic votammetry was performed on 0.5 mM (per manganese) methanol/aqueous (90/10, v/v) solutions of the compounds investigated.
  • the ionic strength was kept at 0.10 M (NaCl), and 0.05 M tris buffer was used for pH adjustment.
  • the measured Ei ⁇ was 170 mV more positive in methanolic than in aqueous solution and this value was used to predict the redox potential in aqueous solution from measurement in methanol/aqueous solution.
  • Mn m TM-2-PyP 5+ was added as an internal standard when cyclic voltammetry of ⁇ Mn ⁇ BVDME ⁇ 2 in methanol was performed.
  • the chronocoulometry measurements were performed by recording the change in charge vs time at a fixed potential that was applied to a glassy-carbon button working electrode immersed in lmM methanol/aqueous (90/10, v/v) solutions (0.1 M NaCl, 0.05 M tris buffer, pH * 7.9) of l/2 ⁇ Mn ra BVDME ⁇ 2 and Mn TM-2-PyP 5+ .
  • E. coli strains AB1157 (SOD-proficient, wild type) and JI132 (SOD-deficient, sodAsodB) were obtained from J. A. Imlay (Imlay et al, /. Bacteriol. 169:2967 (1987)).
  • the effect of BVDME 3" and ⁇ Mn !II BVDME ⁇ 2 on the growth of these strains was followed aerobically in minimal (five amino acids) medium (Faulkner et al, J. Biol. Chem. 269:23471 (1994)). Cultures were treated as previously described (Faulkner et al, J. Biol. Chem.
  • Carboxyl groups are separated from the main chromophores by two methylene groups, so that their ionization is not detectable spectrophotometrically.
  • the spectra of biliverdin and its ester are the same (Gray et al, J. Chem. Soc. 2276 (1961); Kuenzle et al, Biochem. J. 130:1147 (1972); O'Carra, Nature 899 (1962)).
  • metal to ligand ratio (20 ⁇ M)
  • the formation of the complex ⁇ Mn ra BVDME ⁇ 2 at pH * 7.4 methanol/aqueous, 90/10, v/v
  • a very slow hydrolysis of ⁇ Mn ffl BVDME ⁇ 2 occurs in 90/10 methanol/aqueous solution, pH * 7.9.
  • pH * 7.9 A very slow hydrolysis of ⁇ Mn ffl BVDME ⁇ 2 occurs in 90/10 methanol/aqueous solution, pH * 7.9.
  • a week at 25 °C, only 14% of the complex dissociated.
  • the 1 ⁇ M ⁇ Mn BVDME ⁇ 2 was stable in the presence of a 900-fold excess EDTA (0.9 mM) for 24 hours at 25 °C in methanol/aqueous (90/10, v/v) solution, 0.05 M tris, pH * 7.9.
  • Electrospray Mass Spectrometry The dimeric structure of manganese(HI) biliverdin dimethylester (Fig. 2) is neutral and can only be observed in ESMS by association with cations, presumably at enolic oxygens or by metal-centered electrochemical oxidation at the capillary tip (The Electrolytic Nature of Electrospray by Van Berkel, G. J. in Electrospray Ionization Mass Spectrometry, Fundamentals, Instrumentation, And Applications, Cole, B. R., editor, John Wiley & Sons, Inc., New York 1997, pp 65)).
  • Manganese(IU) biliverdin dimethylester does not have an easily available Mn(HI)/Mn( ⁇ ) couple, but does have an easily available Mn(UJ)/Mn(rV) redox.
  • the cationic aquamanganese(i ⁇ ) and monohydroxoiron(HI) N-alkylpyridyl porphyrins can be easily reduced at the metal centers as a consequence of their positive E ⁇ /2 (Batinic-Haberle et al, Inorg. Chem. 38:4011 (1999); Batinic-Haberle et al, J. Porphyrins Phthalocyanines 4:217 (2000)). Consequently, their mass spectra contain peaks of reduced species whose intensities depend upon the applied cone voltage.
  • Fig. 5A Examples of the ESMS spectra are given in Fig. 5A and the assignment of the peaks in Table 2.
  • Fig. 5B the intensities of the major ions are given as a function of cone voltage. The isotopic distribution was accounted for in the calculation of ion intensities.
  • the spectrum shows two major peak groups of similar relative intensities, one around m/z 1325 and the other region around m/z 662.
  • the dominant peak at m/z 1325 is assigned to the protonated dimeric structure ⁇ Mn ffl BVDME,Mn ffl HBVDME + ⁇ , and the peak at m/z 1324 to the species oxidized at the metal site,
  • the ratio of oxidized to cationic dimer decreases, whereas consequently the ratio of oxidized to cationic monomer increases.
  • the dimer persists with the cone voltage as high as 180 V, which is indicative of its high stability, and of its covalent nature. At cone voltage approaching 180 V, more of the ligand becomes detectable at m/z 611.
  • the peaks at m/z 1987 and m/z 1988 may be assigned either to the oxidized and protonated (monomer+dimer) cluster, or to the oxidized or protonated trimer, respectively.
  • the singly charged manganese(UI) salen was also prepared which was previously characterized as containing manganese in the trivalent state (Boucher, /. Inorg. Nucl. Chem. 36:531 (1974)).
  • the magnetic susceptibility of Mn ⁇ OBTM- 4-PyP 4 * was measured, the metal of which is in the divalent state (Batinic-Haberle et al, Arch. Biochem. Biophys. 343:225-233 (1997)).
  • the magnetic moments are given in Table 3. In all cases, independently of the total charge of the compounds, the ⁇ eff are lower in methanol than in water.
  • the measured gram susceptibilities ( ⁇ g ) of ⁇ Mn ⁇ BVDME ⁇ were independent of magnetic field strength from 300 to 3000 Oe at both 77 K and 286 K, indicating the absence of ferromagnetic impurities in the compound.
  • Sixty ⁇ g values were obtained from 77 K to 286 K, and Fig. 7 shows the linear relationship between ⁇ g and 1/(T + 27.1), in accord with the Curie- Weiss law (eq 3)
  • ⁇ g C / (T + ⁇ ) + ⁇ d [3]
  • the diamagnetic gram susceptibility, ⁇ d obtained from the intercept was (-1.18 + 1.44) x 10 "7 emu/g.
  • N is the number of manganese ions/g
  • the magnetic moment ⁇ was calculated to be 4.45 BM (Table 3).
  • the Weiss constant of -27.1 K indicates antiferromagnetic interactions between the manganese centers in the solid.
  • Electrochemistry At 0.1 V/s scan rate and in the + 0.6 to -0.4 V region, cyclic voltammetry of ⁇ Mn ffl BVDME ⁇ as compared to metal-free ligand BVDME 3" , reveals two new waves, one reversible and the other one irreversible (Fig. 8). The irreversible wave seen at more negative potentials, becomes reversible at higher scan rates (see below).
  • the magnetic moment ⁇ eff 5.10 BM, shown in Table 3, established +3 (Physical Methods for Chemists, Drago, R. S., 2nd Ed., Saunders College Publishing. Ft.
  • Two metallotetrapyrroles were tested for antioxidant activity, in vitro.
  • the compounds were assayed for their ability to dismutate superoxide in the indirect method that utilizes xanthine and xanthine oxidase to generate superoxide and cytochrome c reduction as indicator of superoxide flux. Both compounds could dismutate superoxide with the MnBVDME being more potent than the MnBRDT (manganese (III) bilirubin ditaurate - see Fig. 14).
  • MnBRDT manganese (III) bilirubin ditaurate - see Fig. 14
  • the compounds were also assayed for their ability to prevent lipid peroxidation of rat brain homogenates by iron and ascorbate.
  • the mixture of iron and ascorbate generates reactive oxygen species that oxidize biological lipids and these oxidized lipids can be detected as species that react with thiobarbituric acid (TBARS). Both compounds could inhibit the formation of TBARS and this ability correlated with their superoxide dismutase (SOD) activity (Table 5).
  • m/z 1005 and m z 1017 may be assigned to doubly charged protonated ⁇ Mn m HB ⁇ ME".Mn m BVON-lE. ⁇ to a HBVDMir ⁇ . mixed protonated and sodiated ⁇ Mn m HBVOr ⁇ Mn 2I BVD. ⁇ E.Mn :II NaBVDME " ⁇ and sodiated trimer ⁇ Mn m NaBVDME'.Mn m B ⁇ ONE.Mn ! ⁇ aBVD E " . respectively.

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Abstract

L'invention concerne, de façon générale, un procédé de modulation de processus physiologiques et pathologiques et, en particulier, un procédé de modulation de niveaux cellulaires d'oxydant et, de ce fait, des processus dans lesquels ces oxydants jouent un rôle. Elle concerne également des composés et des compositions pouvant être mis en application avantageusement dans ces procédés.
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US6127356A (en) 1993-10-15 2000-10-03 Duke University Oxidant scavengers
CA2309154C (fr) 1997-11-03 2010-02-16 Duke University Porphyrines substituees
AU771259B2 (en) 1998-04-24 2004-03-18 Aeolus Sciences, Inc. Substituted porphyrins
ATE552260T1 (de) 1999-01-25 2012-04-15 Nat Jewish Health Substituierte porphyrine und deren therapeutische verwendung
US6902881B2 (en) 2000-10-13 2005-06-07 President And Fellows Of Harvard College Compounds and methods for regulating cell differentiation
US6908732B2 (en) 2000-10-13 2005-06-21 President & Fellows Of Harvard College Compounds and methods for regulating cell differentiation
EP1404318A2 (fr) * 2000-11-10 2004-04-07 The President and Fellows of Harvard College Composes et procedes permettant de reguler la differentiation cellulaire
AU2002312194B8 (en) 2001-06-01 2008-05-15 Aeolus Sciences, Inc. Oxidant scavengers for treatment of diabetes or use in transplantation or induction of immune tolerance
EP1513537A4 (fr) 2002-06-07 2006-09-06 Univ Duke Porphyrines substituees
US7807825B2 (en) 2004-02-09 2010-10-05 Duke University Substituted porphyrins
WO2007103427A2 (fr) * 2006-03-06 2007-09-13 Wang Xiang H Usage médical de bilirubine et d'analogues structuraux de celle-ci
JP4906583B2 (ja) * 2007-05-15 2012-03-28 株式会社日本自動車部品総合研究所 燃料性状検出装置
EP2732817B1 (fr) 2008-05-23 2016-08-24 National Jewish Health Composé destiné à être utilisé dans le traitement d'une lésion associée à l'exposition à du phosgène ou du chlore gazeux
US8455222B2 (en) 2009-11-04 2013-06-04 Utah State University Biliverdin from a non-animal source
US9119842B2 (en) 2012-09-14 2015-09-01 Utah State University Therapeutic meso-biliverdin IXα compositions and associated methods
CN105693702B (zh) * 2016-01-15 2019-08-16 新疆大学 一种吡唑啉酮缩呋喃酰肼合铜配合物的制备及生物活性
KR102254093B1 (ko) 2017-05-12 2021-05-20 주식회사 빌릭스 빌리루빈 유도체 및 금속을 포함하는 입자
CN109535057B (zh) * 2018-11-07 2020-03-10 百顺药业有限公司 一种用胆绿素Ⅸα二酯制备高含量胆红素Ⅸα的方法
CN112479967B (zh) * 2020-12-22 2023-07-21 百顺药业有限公司 胆绿素类化合物及其制备方法和用途
CN112624953B (zh) * 2020-12-22 2023-07-21 百顺药业有限公司 胆绿素或其衍生物的制备方法

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