WO2007104790A1 - Autoimmune conditions and nadph oxidase defects - Google Patents
Autoimmune conditions and nadph oxidase defects Download PDFInfo
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- WO2007104790A1 WO2007104790A1 PCT/EP2007/052457 EP2007052457W WO2007104790A1 WO 2007104790 A1 WO2007104790 A1 WO 2007104790A1 EP 2007052457 W EP2007052457 W EP 2007052457W WO 2007104790 A1 WO2007104790 A1 WO 2007104790A1
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- 0 CC(C)=CCN(*)* Chemical compound CC(C)=CCN(*)* 0.000 description 3
- BZXDQAJQUWALFQ-UHFFFAOYSA-N CC(C)=CCC(CC=C(C)C)(N)N=C Chemical compound CC(C)=CCC(CC=C(C)C)(N)N=C BZXDQAJQUWALFQ-UHFFFAOYSA-N 0.000 description 1
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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Definitions
- the present disclosure relates to methods and materials involved in treating, preventing, and ameliorating one or more conditions associated with autoimmune conditions.
- the present disclosure relates to methods and materials involved in treating, preventing, or delaying the onset of arthritis and multiple sclerosis.
- Autoimmune conditions are conditions where a mammal's immune system reacts against its own tissues. Such conditions include, without limitation, arthritis (e.g., rheumatoid arthritis (RA)), multiple sclerosis (MS), inflammatory bowel disease, Crohn disease, lupus, autoimmune uveitis, type I diabetes, bronchial asthma, septic arthritis induced with staphylococci or streptococci, and cardiovascular disease involving vasculitis.
- arthritis e.g., rheumatoid arthritis (RA)
- MS multiple sclerosis
- inflammatory bowel disease Crohn disease
- lupus inflammatory bowel disease
- Crohn disease Crohn disease
- lupus inflammatory bowel disease
- lupus e.g., rupus
- autoimmune uveitis e.g., type I diabetes, bronchial asthma, septic arthritis induced with staphylococci or streptococci
- RA is a chronic inflammatory disease that can be found in about 1-2 % of the population. RA primarily affects peripheral joints where inflammatory synovitis leads to cartilage destruction, bone erosion, and ultimately to joint deformity and loss of joint function. RA is a complex disease in that both environmental factors as well as multiple chromosomal regions are involved in susceptibility to RA.
- Inducers of arthritis in animal models include adjuvants, collagen (e.g., collagen type II) (collagen induced arthritis (CIA)), hexadecane (hexadecane induced arthritis (HIA)), oil (e.g., Freund's incomplete adjuvant), squalene (squalene induced arthritis (SIA), and pristane (pristane induced arthritis (PIA)).
- collagen e.g., collagen type II
- HOA hexadecane induced arthritis
- oil e.g., Freund's incomplete adjuvant
- squalene squalene induced arthritis
- PIA pristane induced arthritis
- Chromosomal regions known to be associated with development of RA include the major histocompatibility complex region.
- different genomic regions are known to control different phases of the disease such as onset, severity during the acute onset phase, and the severity of the destruction in the chronic relapsing phase.
- MS is a chronic inflammatory disease of the central nervous system.
- the characteristic pathological feature is demyelination of the myelin sheath of neurons in the central nervous system, resulting in multiple and varied neurologic symptoms and signs, usually with repeated relapse and remission.
- MS affects more than 2 million people worldwide.
- Studies have implicated a cell-mediated immune response, involving T cells recognizing epitopes of myelin basic protein (MBP), in the pathogenesis of MS.
- MBP myelin basic protein
- Experimental autoimmune encephalomyelitis (EAE) is an autoimmune inflammatory and demyelinating disease model that shares many clinical and histological features with MS. EAE can be induced in susceptible strains of mice by immunization with self antigens derived from myelin.
- the Ncf 1 gene encoding the p47phox subunit of the NADPH oxidase complex, has been shown to be associated with the development of arthritis in the DA rat. (Olofsson et al. (2003) Nature Genetics 33:25-32; WO 03/095667), and the development of arthritis and encephalomyelitis in mice (Hultqvist et al. (2004) Proc NatlAcad Sci U SA. 101:12646-51).
- autoimmune conditions such as arthritis (e.g., RA), multiple sclerosis, lupus, autoimmune uveitis, type I diabetes, bronchial asthma, septic arthritis induced with staphylococci or streptococci, and cardiovascular disease involving vasculitis.
- arthritis e.g., RA
- multiple sclerosis lupus
- autoimmune uveitis type I diabetes
- bronchial asthma septic arthritis induced with staphylococci or streptococci
- cardiovascular disease involving vasculitis e.g., this disclosure provides methods and materials involved in treating, preventing, ameliorating one or more symptoms associated with, and/or delaying the onset of autoimmune conditions.
- the inventions described herein are based on the discovery that arthritis can be associated with or caused by a reduced level of NADPH oxidase activity.
- development of severe arthritis symptoms in an arthritis animal model can be, at least partially, dependent upon the presence of low NADPH oxidase activity.
- the inventions are based on the discovery that mammals prone to develop arthritis can be protected by providing those mammals with normal or increased levels of NADPH oxidase activity.
- the inventions are also based on the discovery that compounds that include one or more isoprenoid units (e.g., one or more unsaturated isoprenoid units and/or one or more saturated isoprenoid units) can be used as NADPH activators.
- NADPH activators can be useful for treating, lessening the severity of the symptoms of, preventing, or delaying the onset of symptoms of an autoimmune condition in an animal such as a mammal.
- the compounds include at least one unsaturated isoprenoid unit or saturated isoprenoid unit that is derivatized with a functional moiety.
- a variety of compound classes useful as NADPH activators are described in more detail below (e.g., in compound classes 1-46).
- the invention features compounds; compositions (e.g., pharmaceutical compositions) containing the compounds described herein; and methods for treating a mammal having an autoimmune condition (e.g., arthritis or multiple sclerosis) or ameliorating one or more symptoms of the autoimmune condition in such a mammal.
- an autoimmune condition e.g., arthritis or multiple sclerosis
- the compounds described herein for treating a mammal can be NADPH oxidase activators.
- the compounds can include up to 10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, one or more isoprenoid units (e.g., one or more unsaturated isoprenoid units and/or one or more saturated isoprenoid units) conjugated to one another, in which the isoprenoid units can be arranged in any sequence or directionality (e.g., head to tail, head to head, tail to tail) relative to one another.
- One or more of the isoprenoid units e.g., one or more unsaturated isoprenoid units and/or one or more saturated isoprenoid units
- the compounds can include derivatized isoprenoid units (e.g., derivatized unsaturated isoprenoid units and/or derivatized saturated isoprenoid units) arranged in any sequence or directionality relative to one another and in any sequence or directionality relative to underivatized isoprenoid units (e.g., unsaturated isoprenoid and/or underivatized saturated isoprenoid units).
- derivatized isoprenoid units e.g., derivatized unsaturated isoprenoid units and/or derivatized saturated isoprenoid units
- underivatized isoprenoid units e.g., unsaturated isoprenoid and/or underivatized saturated isoprenoid units.
- the compounds may be administered intra-dermally, intra-peritoneally, orally, or intra-nasally.
- the invention features the use of one or more of the compounds described herein in the manufacture of a medicament to treat, prevent, delay the onset of one or more symptoms, or ameliorate one or more symptoms of an autoimmune condition (e.g., arthritis or multiple sclerosis), wherein the composition enhances NADPH oxidase activity in a mammal.
- an autoimmune condition e.g., arthritis or multiple sclerosis
- the compounds can have any of the structural formulae delineated herein including, e.g., the structural formulae associated with compound classes 1-46.
- Another embodiment of the invention features a method of formulating a medicament for the treatment of an autoimmune condition, the method including: (a) contacting a sample comprising cells or a cellular fraction having NADPH activity with a test composition, (b) determining the level of NADPH oxidase activity in the sample, (c) determining whether or not the level is greater than a control level of NADPH oxidase activity, wherein the control level is the amount of NADPH oxidase activity in a control sample lacking the test composition, (d) identifying the test composition as a composition useful for treatment of the autoimmune condition when the level of NADPH oxidase activity is greater than the control level, and (e) formulating a medicament from the composition for the treatment of the autoimmune condition.
- the autoimmune condition can be arthritis or multiple sclerosis.
- Test compounds can have any of the structural formulae delineated herein including, e.g., the structural formulae delineated in compound classes 1-46.
- this invention features a method for treating a mammal having an autoimmune condition, the method includes administering to the mammal (e.g., a mammal in need thereof) a compound, or a pharmaceutically acceptable salt thereof, that enhances NADPH oxidase activity, wherein said compound includes one or more isoprenoid units.
- the autoimmune condition can be arthritis or multiple sclerosis.
- this invention features the compounds delineated herein (e.g., genera, subgenera, or specific compounds set forth in compound classes 1-46).
- this invention features a pharmaceutical composition, which includes one or more of the compounds delineated herein (e.g., genera, subgenera, or specific compounds set forth in compound classes 1-46) or a salt (e.g., a pharmaceutically acceptable salt) or a prodrug thereof and a pharmaceutically acceptable adjuvant, carrier or diluent.
- the composition can include an effective amount of the compound or the salt thereof.
- the composition can further include an additional therapeutic agent.
- Embodiments can include one or more of the following features.
- the compound can include one or more unsaturated isoprenoid units.
- the compound can include one or more saturated isoprenoid units.
- at least one of said unsaturated isoprenoid units or saturated isoprenoid units can be derivatized with a functional moiety.
- the compound can have the following general formula:
- compound classes 1-46 e.g., compound classes 1, 2, 13, 45, or 46.
- each of these variables can be independently of one another, H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which being optionally substituted as described herein.
- R' can be hydrogen.
- R' can be Ci-C 6 alkyl (e.g., CH 3 ).
- One of m and n can be 0.
- the other of m and n can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3 (e.g., 2-4).
- n can be 0, and m can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- m can be 0, and n can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- m + n 3.
- One of m and n can be 0 (e.g., n can be 0, and m can be 3 or vice versa).
- m + n 2.
- One of m and n can be 0 (e.g., n can be 0, and m can be 2 or vice versa).
- the compound can be selected from the group consisting of: (3,7,1 l,15-Tetramethyl-2-hexadecen-l-ol); Farnesol (3,7,1 l-Trimethyl-2,6,10-dodecatrien-l-ol); Geranylgeraniol (3,7,11,15-Tetramethyl-hexada- 2,6,10,14-tetraen-l-ol); Farnesyl acetate (Acetic acid 3,7,1 l-trimethyl-dodeca-2,6,10-trienyl ester); Phytyl acetate (Acetic acid 3,7,1 l,15-tetra-metyl-hexadec-2-enyl-ester); Di-hydro-phytol (3,7,11,15-Tetramethyl-hexadecan-l-ol); and Di-hydro-phytyl acetate (Acetic acid 3,7,11,15-tetra
- the compound can have the general formula:
- R' can be H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted (e.g., R' can be hydrogen; optionally substituted alkyl, optionally substituted aryl; or heteroaryl). In certain embodiments, R' can be hydrogen.
- one of m and n can be 0.
- the other of m and n can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3 (e.g., 2-4).
- n can be 0, and m can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- m can be 0, and n can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- m + n 3.
- One of m and n can be 0 (e.g., n can be 0, and m can be 3 or vice versa).
- m + n 2.
- One of m and n can be 0 (e.g., n can be 0, and m can be 2 or vice versa).
- the compound can be 3,7,1 l,15-tetramethyl-l-hexadecen-3-ol.
- the compound has the general formula:
- R' can be H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted (e.g., R' can be hydrogen; optionally substituted alkyl, optionally substituted aryl; or heteroaryl, e.g., R' can be hydrogen or optionally substituted alkyl). In certain embodiments, R' can be optionally substituted alkyl.
- one of m and n can be 0.
- the other of m and n can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- n can be 0, and m can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- m can be 0, and n can be an integer from 1-9, e.g., 1-5, 1-4, 2-5, 2-4, 2 or 3.
- m + n 3.
- One of m and n can be 0 (e.g., n can be 0, and m can be 3 or vice versa).
- m + n 2.
- One of m and n can be 0 (e.g., n can be 0, and m can be 2 or vice versa).
- R' can be C 1 -C 3 alkyl substituted with from 1-3 (e.g., 2) halogens, (e.g., fluoro (F).
- 1-3 e.g., 2) halogens, (e.g., fluoro (F).
- the compound can be 6-Difluoromethoxy-2,5,7,8-tetramethyl-2-(4,8,12- trimethyl-tridecyl)-chroman.
- the compound can be administered intra-dermally, intra-peritoneally, orally, or intra-nasally.
- all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
- the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
- Figures IA-E set forth synthetic reaction schemes for using and preparing the compound classes described herein.
- the bolded number underneath a compound corresponds to the particular compound class, while R, R', R", and R'" convey one or more isoprenoid units and/or one or more saturated isoprenoid units conjugated to one another.
- Figure 2 is a graph illustrating oxidative burst of granulocytes after in vitro stimulation with compound 1 (phytol) ( ⁇ ),compound 2 (farnesol) (•), compound 3 (geranyl geraniol) (A) or pristane (O).
- Figure 4 is a set of bar graphs illustrating the tissue distribution of 3H-labeled compound 1 (phytol) at day 2, 4, 8, 11, and 17 post-injection.
- Figure 5 is a graph demonstrating the severity of PIA in DA.Ncfl DA rats treated with injection of compound 1 (phytol) (A) compared with untreated DA.Ncfl DA rats ( ⁇ ).
- A compound 1
- ⁇ untreated DA.Ncfl DA rats
- Figure 6 is a set of graphs illustrating the effect of treatment of established PIA with compound 1 (phytol).
- Figure 6 A demonstrates the severity of arthritis in DA.Ncfl D ⁇ rats after injections of compound 1 at the estimated peak of disease (day 22). (Significance indications above line represent s.c. administration and below i.p. administration) (control ( ⁇ ), compound 1 (phytol) i.p (O), compound 1 (phytol) s.c. (A)). *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
- Figure 6B shows the effect of injections of compound 1 on serum levels of COMP (ng/ml).
- Figure 6C demonstrates the severity of arthritis in DA.Ncfl DA rats after injections of compound 1 in the chronic phase, (control ( ⁇ ) and compound 1 (phytol) s.c. (A)), *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
- Figure 6D demonstrates the effect of injections of compound 1 on the severity of arthritis in Lewis.IF rats (control ( ⁇ ) and compound 1 (phytol) s.c. (A)), *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
- Figure 6E demonstrates the effect injections of compound 1 on the severity of arthritis in rats with a functional oxidative burst (control ( ⁇ ) and compound 1 (phytol) (A)), *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
- Figure 7 is a set of graphs illustrating the effect of compound 1 (phytol) on collagen induced arthritis in DA.Ncfl DA rats.
- Figure 7B shows the level of CII antibodies in serum.
- Figure 8 is a set of graphs illustrating the effect of compound 1 (phytol) on non oil collagen induced arthritis in DA.Ncfl D ⁇ rats.
- Figure 9 is a graph demonstrating the severity of PIA in DA.Ncfl DA rats treated with injections of compound 1 (phytol) ( ⁇ ) or compound 5 (phytyl acetate) (A). Untreated control (O).
- Figure 10 is a graph demonstrating the severity of PIA in DA.Ncfl D ⁇ rats treated with injections of compound 1 (phytol) ( ⁇ ) or compound 8 (A). Untreated control (O).
- Figure 11 is a graph demonstrating the severity of PIA in DA.Ncfl D ⁇ rats treated with injections of compound 2 (farnesol) ( ⁇ ) or compound 4 (farnesyl acetate) (A). Untreated control (O).
- Figure 12 is a graph demonstrating the severity of PIA in DA.Ncfl DA rats treated with injections of compound 1 (phytol) ( ⁇ ), compound 6 (di-hydro-phytol ( ⁇ ), compound 5 (phytyl acetate) (A) or compound 7 (di-hydro-phytyl acetate (•XUntreated control (O).
- Figure 13 is a graph demonstrating the severity of PIA in DA.Ncfl D ⁇ rats treated with oral administration of phytol 1% daily (7202244831), phytol 1% every 2'nd day (A), or phytol 1% initiated day 7 after arthritis induction. Untreated control (O), 0mega3 fatty acid (D).
- Figure 14 is a graph demonstrating the severity of PIA in DA.Ncfl DA rats treated with oral administration of compound 1 (phytol) 1% daily ( ⁇ ) or compound 5 (phytyl acetate) 1% daily (A). Untreated control (O).
- Figure 15 is a graph illustrating oxidative burst of granulocytes after in vitro stimulation with compound 1 (phytol) ( ⁇ ), compound 2 (farnesol) (A) or compound 9 (isophytol) (•).
- Figure 16 is a graph demonstrating the severity of PIA in DA.Ncfl D ⁇ rats treated by oral gavage with compound 1 (phytol) 1.6 g/kg/every second day ( ⁇ ), compound 1 (phytol) 3.2 g/kg/every second day (A) or untreated control (O).
- Figure 17 is a graph demonstrating the severity of PIA in DA.Ncfl D ⁇ rats treated with oral administration of compound 1 (phytol) 500 mg/kg/day ( ⁇ ), compound 9 (isophytol) 500 mg/kg/day (A), or fenofibrate 100mg/kg/day (D) or untreated control (O).
- Figure 18 is a graph demonstrating the effect of compound 1 (phytol) on the development of EAE in DA.Ncfl D ⁇ rats treated with parenteral administration of compound 1 (phytol) ( ⁇ ) or untreated control (O).
- the invention provides methods and materials related to treating autoimmune conditions (e.g., arthritis and multiple sclerosis).
- autoimmune conditions e.g., arthritis and multiple sclerosis.
- compounds that include one or more one or more isoprenoid units e.g., one or more unsaturated isoprenoid units and/or one or more saturated isoprenoid units
- compositions e.g., pharmaceutical compositions, containing such compounds; and methods for using the same to treat or to alleviate the symptoms of autoimmune disease are described.
- the invention provides compounds useful for treating autoimmune diseases.
- the compounds can enhance NADPH oxidase activity.
- pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof.
- Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
- the compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
- salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N- methylglucamine, procaine, N-benzylphenethylamine, l-para-chlorobenzyl-2- pyrrolidin-l'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, nitrates, borates, me
- esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
- Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
- treatment means any manner in which one or more of the symptoms of an autoimmune condition, such as arthritis or multiple sclerosis, are ameliorated or otherwise beneficially altered.
- Treatment also encompasses any pharmaceutical use of the compounds or compositions herein, such as uses for treating diseases, disorders, or ailments in which an autoimmune condition is suspected or implicated, e.g., in a mammal such as a human.
- amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
- a compound typically includes one or more isoprenoid units, and more specifically one or more unsaturated isoprenoid units and/or one or more saturated isoprenoid units.
- isoprenoid unit refers to a five carbon unit that is represented by the structure:
- saturated isoprenoid unit refers to a five carbon unit that is represented by the structure:
- saturated isoprenoid unit refers to a five carbon unit that is represented by the structure:
- the right most line i.e., the line that extends rightward from the "head” of the isoprenoid unit and having the terminus labelled with the asterisk (*)
- each of the above three structural representations is intended to represent a covalent bond that can occur (i) between the "head" terminus of said isoprenoid unit and, e.g., a tail or head terminus of another unsaturated or saturated isoprenoid unit; or (ii) between the "head" terminus of said isoprenoid unit and an atom that forms part of another structural moiety, e.g. a functional moiety (i.e., the terminus marked with the asterisk (*) in the aforementioned structures is not intended to show a sixth carbon atom attached to the head of said isoprenoid unit).
- a compound that contains a saturated isoprenoid unit that is directly connected, in head to tail fashion, to an unsaturated isoprenoid unit would have the following structure:
- the bolded line in the above 10-carbon structure represents the covalent bond between the head terminus of the saturated isoprenoid unit and the tail terminus of the unsaturated isoprenoid unit.
- the unsaturated isoprenoid and/or saturated isoprenoid units can be conjugated (e.g., covalently bound) to one another.
- brackets around an unsaturated isoprenoid and/or saturated isoprenoid unit structure represent the ability of a unit to be conjugated at either the head or tail termini, e.g., to another unit.
- a compound can include up to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 2, 3, or 4, e.g., 2 or 3, e.g. 3) unsaturated isoprenoid units and/or saturated isoprenoid units conjugated to one another.
- a compound can include unsaturated isoprenoid units and/or saturated isoprenoid units arranged in any sequence or directionality relative to one another.
- one or more of the unsaturated isoprenoid units and/or saturated isoprenoid units can be derivatized with one or more functional moieties.
- a compound can include derivatized unsaturated isoprenoid units and/or derivatized saturated isoprenoid units arranged in any sequence or directionality relative to one another and in any sequence or directionality relative to underivatized unsaturated isoprenoid units and/or underivatized saturated isoprenoid units.
- a derivatized unsaturated isoprenoid unit or a derivatized saturated isoprenoid unit can be at any position in a compound, e.g., at an internal or at a terminal unit.
- a compound can include a saturated isoprenoid unit conjugated to an unsaturated isoprenoid unit, which is in turn conjugated to a derivatized (saturated or unsaturated) isoprenoid unit.
- a compound can include three saturated isoprenoid units, with the second saturated isoprenoid unit conjugated to the third derivatized saturated isoprenoid unit.
- a functional moiety can be conjugated (e.g., covalently bound) to an unsaturated isoprenoid unit and/or saturated isoprenoid unit at any carbon position in the unit, e.g., at a terminal, branching, or internal carbon atom of the unit.
- a functional moiety can comprise any functional group, including, without limitation, alkyl, alkenyl, alkynyl, cycloalkyl, alcohol, ketone, aldehyde, carboxylic acid, carboxylic acid ester, thio ester, carbamate, halide, alkyl ether, aryl ether, thio ether, amine, amide, heterocyclic (e.g., piperazinyl), heteroaryl (thienyl, furyl, pyridyl) or aryl (e.g., phenyl or naphthyl) groups, or combinations thereof.
- alkyl alkenyl, alkynyl, cycloalkyl, alcohol, ketone, aldehyde, carboxylic acid, carboxylic acid ester, thio ester, carbamate, halide, alkyl ether, aryl ether, thio ether, amine, amide, heterocyclic (e.g.,
- alkyl refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
- Ci- 20 -alkyl denotes a straight or branched alkyl group having from 1 to 20 carbon atoms.
- alkyl include methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
- Ci- 20 -alkyl For parts of the range "Ci- 20 -alkyl" all subgroups thereof are contemplated (e.g., C 1 -C 12 , Ci-Cio, C 1 -C 6 , or C 1 -C 3 linear or branched saturated chains).
- alkenyl refers to a straight or branched hydrocarbon chain containing 2-20 carbon atoms and having one or more double bonds.
- alkynyl refers to a straight or branched hydrocarbon chain containing 2-20 carbon atoms and having one or more triple bonds. Examples of said alkenyl include vinyl, allyl, 1-butenyl, 1- pentenyl, and 1-hexenyl. Examples of alkynyl include ethynyl, propargyl, and 3- hexynyl.
- C 2 - 2 o-alkenyl and "C 2-2 o-alkynyl,” all subgroups thereof are contemplated (e.g., C 2 -C 12 , C 2 -C 1 O, C 2 -C 6 , or C 2 -C 4 linear or branched).
- cycloalkyl refers to saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon C 3 -C 2 O (e.g., C 3 -Ci 0 , C 3 -C 8 , C 3 -C 6 ) rings. Cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom.
- Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicycle [2.2.1] hep tyl).
- Alkyl, alkenyl, alkynyl, and cycloalkyl groups can be optionally substituted (e.g., with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents, e.g., X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, alkyl, cycloalkyl, or carboxylic acid ester moieties (or any combination thereof).
- substituents e.g., X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, alkyl, cycloalkyl, or carboxylic acid ester moieties (or any combination thereof).
- aryl refers to a hydrocarbon ring System having at least one aromatic ring.
- aryls are phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl.
- Aryl groups may be substituted optionally with one or more (e.g., with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents such as X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, alkyl (e.g.,CH 3 ), or carboxylic acid ester moieties (or any combination thereof when more than one substituent is present).
- substituents such as X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, alkyl (e.g.,CH 3 ), or carboxylic acid ester moieties (or any combination thereof when more than one
- heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring System (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring System.
- heteroaryl rings examples include pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline (i e 2,3-dihydroindole), isoindoline (i e 1,3-dihydroisoindole), benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzodioxole, benzothiadiazole, benzotriazole, benzox
- Heteroaryl groups may be substituted optionally with one or more(e.g., with from 1-5 (e.g., 1-4, 1- 3, 1-2, or 1) substituents such as X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, CH 3 , or carboxylic acid ester moieties (or any combination thereof when more than one substituent is present).
- substituents such as X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, CH 3 , or carboxylic acid ester moieties (or any combination thereof when more than one substituent is present).
- heterocyclic and “heterocyclyl” in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms having one or more heteroatoms (e.g., oxygen, sulfur, or nitrogen) as part of the ring System and the reminder being carbon, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings.
- heteroatoms e.g., oxygen, sulfur, or nitrogen
- Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,4-oxazepane, azepane, phthalimide, indoline, isoindoline, 1 ,2,3,4-tetrahydroquinoline, 1 ,2,3,4-tetrahydroisoquinoline, hexahydroazepine, 3,4-dihydro-2(lH)isoquinoline, 2,3-dihydro-lH-indole, 1,3-dihydro- 2H-isoindole, azocane, l-oxa-4-azaspiro[4.5]dec-4-ene, decahydroisoquinoline, 1,2- dihydroquinoline, and 1,4-diazepane.
- Heterocyclic groups groups may be substituted optionally with one or more(e.g., with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents such as X (e.g., F, Cl, Br, I), NH 2 , NO 2 , CN, OH, CH 3 , or carboxylic acid ester moieties (or any combination thereof when more than one substituent is present).
- substituents e.g., F, Cl, Br, I
- NH 2 , NO 2 , CN, OH, CH 3 or carboxylic acid ester moieties (or any combination thereof when more than one substituent is present).
- Compound class 1 includes branched alcohols having the general formula:
- n+m is an integer from 0 to 9.
- Particular species include:
- Compound class 2 includes carboxylic acid esters having the general formula:
- n+m is an integer from 0 to 9; and where R' can be, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- R' can be, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- Particular compounds include:
- Hexadecanoic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Phytyl palmitate);
- Octadecanoic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Phytyl stearate);
- Citric acid tri-(3,7,l l-trimethyl-dodeca-2,6,19-trienyl) ester Tri-farnesyl citrate
- Nicotinic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Phytyl nicotinate);
- Furan-2-carboxylic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Phytyl-2-furoate);
- Compound class 3 includes carbamates with the general formula:
- n+m can be an integer from 0 to 9; and where R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- Particular examples include:
- Phenyl carbamic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Phytyl N-phenyl carbamate);
- Furan-2-yl carbamic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Phytyl N-furan-2-yl carbamate);
- Compound class 4 substitutes a halogen moiety for the hydroxy moiety in composition class 1.
- Halogen moieties include F, Cl, Br, and I.
- Compound class 5 includes aryl ethers with the general formula:
- n+m is an integer from 0 to 9; and Ar is optionally substituted aryl (e.g., phenyl).
- aryl e.g., phenyl
- Compound class 6 includes thio ethers with the general formula:
- n+m is an integer from 0 to 9; and where R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- Particular examples include:
- Compound class 7 include amines with the general formula:
- R' and R" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 8 includes compounds with the general formula:
- R' and R" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 9 includes compounds having the general formula:
- R', R" and R' independently aree.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 10 includes carboxylic acids with the general formula:
- n+m an integer from 0 to 13, exemplified by:
- Compound class 11 includes amides of the general formula:
- R' and R" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 12 includes carboxylic acid esters with the general formula:
- n+m an integer from 0 to 9; and R' is alkyl, aryl, or heteroaryl.
- Examples include:
- Compound class 13 includes branched alcohols with the general formula:
- Compound class 14 includes carboxylic acid esters with the general formula:
- n+m an integer from 0 to 9; and where R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Octadecanoic acid 3,7,11,15-tetramethyl-hexadecyl ester Dihydrophytyl stearate
- Citric acid tri-(3,7,l l,15-tetramethyl-hexadecyl) ester Tri-dihydrophytyl-citrate
- Cyclopenta-l,3-dienecarboxylic acid 3,7,11,15-tetramethyl-hexadecyl ester (Dihydrophytyl cyclopenta- 1 ,3-dienecarboxylate) ;
- Nicotinic acid 3,7,11,15-tetramethyl-hexadecyl ester Dihydrophytyl nicotinate
- Compound class 15 includes carbamates with the general formula:
- R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Ethyl carbamic acid 3,7,11,15-tetramethyl-hexadecyl ester Dihydrophytyl N-ethyl carbamate
- Furan-2-yl carbamic acid 3,7,11,15-tetramethyl-hexadecyl ester Dihydrophytyl N-fyran-2-yl carbamate
- Thiophen-2-yl carbamic acid 3,7,1 l,15-tetramethyl-hexadec-2-enyl ester (Dihydrophytyl N-thiphen-2-yl carbamate).
- Compound class 16 substitutes a halogen moiety for the hydroxy moiety in compound class 13.
- Halogen moieties include F, Cl, Br, and I.
- Compound class 17 includes aryl ethers with the general formula:
- n+m an integer from 0 to 9; and Ar is optionally substituted aryl (e.g., phenyl), exemplified by:
- Compound class 18 includes thio ethers with the general formula:
- n+m an integer from 0 to 9; and where R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 19 includes amines with the general formula:
- R' and R" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- Compound class 20 includes compounds with the general formula:
- R' and R' ' independently are H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 21 includes compounds with the general formula:
- R', R" and R'" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 22 are carboxylic acids having the general formula:
- n+m and integer from 0 to 13, exemplified by:
- Compound class 23 includes amides of the general formula:
- R' and R" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 24 includes carboxylic acid esters with the general formula:
- R' is, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 25 includes compounds with the general formula:
- n+m an integer from O to 9, exemplified by:
- Compound class 27 includes compounds with the general formula:
- n+m an integer from O to 9, exemplified by:
- Compound class 28 includes compounds with the general formula:
- n+m an integer from O to 9, exemplified by:
- Compound class 29 are compounds with the general formula:
- n+m an integer from 0 to 9, exemplified by:
- Compound class 30 include compounds having the general formula:
- n+m an integer from 0 to 9, exemplified by:
- Compound class 31 includes compounds with the general formula:
- n+m an integer from O to 9, exemplified by:
- Compound class 32 are compounds with the general formula:
- n+m an integer from 0 to 9, exemplified by:
- Compound class 33 includes compounds with the general formula:
- n+m an integer from 0 to 9, exemplified by:
- Compound class 34 are compounds having the general formula:
- R' and R" independently are, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted. Examples include:
- Compound class 35 are compounds with the general formula:
- R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 36 are compounds with the general formula:
- n+m an integer from O to 9, exemplified by:
- Compound class 38 are compounds with the general formula:
- R is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 39 are compounds with the general formula:
- R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound 40 includes compounds with the general formula:
- n+m an integer from 0 to 9; exemplified by:
- Compound class 41 are compounds having the general formula:
- R' is , e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 42 are compounds with the general formula:
- R is , e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 43 are compounds with the general formula:
- R' is, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, exemplified by:
- Compound class 44 includes ketones and aldehydes having the general formulas:
- R' can be, e.g., H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
- Particular compounds include:
- Compound class 45 are compounds having the general formula:
- n+m an integer from 0 to 9; and where R' can be , e.g., H; alkyl, alkenyl, alkynyl, cycloalkyl, each of which is optionally substituted (e.g., with halogen); , exemplified by :
- Compound Class 46 are compounds having the general formula:
- n+m an integer from 0 to 9; and where R' can be H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is optionally substituted, exemplified by :
- any of the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.
- Compounds of the invention can be prepared by the methods set forth in Figure 1A-1E.
- Starting materials including isoprenoids, isoprenoid alcohols, polyprenols, terpenes, terpenoids, and terpenols, are available commercially from, e.g., Sigma- Aldrich (St. Louis, MO).
- the invention provides methods, compounds, and compositions containing the compounds for treating, preventing, ameliorating one or more symptoms of, or delaying the onset of an autoimmune condition in a mammal.
- Methods for treating, preventing, delaying the onset of, or ameliorating one or more symptoms of an autoimmune condition include administering a compound that increases the level of NADPH oxidase activity in the mammal, e.g., an NADPH oxidase activator.
- a compound that increases a cell's production of reactive oxygen species can be administered to a mammal with arthritis.
- the invention further provides methods for the use of a compound that increases the level of NADPH oxidase activity in a mammal for the manufacture of a medicament for treating, preventing, delaying the onset of, or ameliorating one or more symptoms of an autoimmune condition.
- autoimmune conditions include, without limitation, arthritis (e.g., rheumatoid arthritis (RA)), multiple sclerosis (MS), inflammatory bowel disease, Crohn disease, lupus, autoimmune uveitis, type I diabetes, bronchial asthma, septic arthritis induced with staphylococci or streptococci, and cardiovascular disease involving vasculitis.
- RA rheumatoid arthritis
- MS multiple sclerosis
- inflammatory bowel disease Crohn disease
- lupus inflammatory bowel disease
- Crohn disease Crohn disease
- lupus inflammatory bowel disease
- lupus inflammatory bowel disease
- lupus inflammatory bowel disease
- lupus inflammatory
- the compounds described herein can be administered in any standard form using any standard method (e.g., in the form of a composition, e.g., a pharmaceutical composition).
- a composition e.g., a pharmaceutical composition
- compounds that increase NADPH oxidase activity can be in the form of tablets or capsules (e.g., time-release capsules) that are taken orally.
- the compounds can be in a liquid form and can be taken orally or by injection.
- the compounds also can be in the form of suppositories.
- compounds that increase NADPH oxidase activity can be in the form of creams, gels, and foams that can be applied to the skin.
- the compounds can in the form of an inhalant that is applied nasally.
- the compounds may be administered intra- dermally, intra-peritoneally, orally, or intra-nasally.
- Compounds that increase NADPH oxidase activity can be administered at any dose that is sufficient to increase NADPH oxidase activity in cells that have low activity. Such doses can be taken over a period of years to prevent and/or delay the progression of the autoimmune condition or to reverse the progression of the autoimmune condition. Doses can be selected based on the effectiveness and toxicity of the particular compound using standard pharmacology techniques.
- the methods of the invention can be applied to a wide range of subjects, e.g., mammals such as humans, non-human primates (e.g., monkeys), horses, cattle, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, hamsters, rats, and mice.
- the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
- the subject can be a mammal. In certain embodiments, the subject is a human.
- a compound or pharmaceutical composition described herein is administered to the subject, e.g., a mammal, such as a mammal suspected of suffering from, or suffering from, an autoimmune condition.
- the compounds of the invention will be suspended in a pharmaceutically-acceptable carrier (e.g., physiological saline) and administered orally or transdermally or injected (or infused) intravenously, subcutaneously, intramuscularly, intraperitoneally, intrarectally, intravaginally, intranasally, intragastrically, intratracheally, or intrapulmonarily. They can be delivered directly to an appropriate affected tissue.
- the dosages of the inhibitory compounds and supplementary agents to be used depend on the choice of the route of administration; the nature of the formulation; the nature of the patient's illness; the subject's size, weight, surface area, age, and sex; other drugs being administered; and the judgment of the attending physician. Suitable dosages are generally in the range of 0.0001-100.0 mg/kg. Wide variations in the needed dosage are to be expected in view of the variety of compounds and supplementary agents available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by i.v. injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization as is well understood in the art. Administrations of compounds and/or supplementary agents can be single or multiple (e.g., 2-, 3-, 4-, 6-, 8-, 10-, 20-, 50-.100-, 150-, or more fold).
- Rat (Rattus norvegicus) strains used in the following experiments included the DA and LEW. IF strains, which are highly susceptible to PIA and EAE, and the E3 strain, which is PIA and EAE-resistant (Bergsteinsdottir et al. (2000) J Immunol 164: 1564-8; Vingsbo et al. (1996) Am J Pathol 149: 1675-83).
- DA, LEW. IF and E3 rats were obtained from Gottinstitut f ⁇ r suitsstierzucht, Hannover, Germany; DA rats purchased from Harlan Netherlands were also used.
- DA.Ncfl D ⁇ rats designates DA rats carrying the Ncf 1 DA allele with impaired NADPH oxidase capacity
- DA.Ncfl E3 rats designates DA rats carrying the Ncf 1 E3 allele with functional NADPH oxidase capacity (Olofsson & Holmdahl (2003) Scand J Immunol 58:155-164).
- Rats All animals were kept in animal facilities that have climate-controlled environments with 12-hour light/dark cycles. Rats were housed in polystyrene cages containing wood shavings and were fed standard rodent chow and water ad libitum. Rats were free from common pathogens, including the Sendai virus, Hantaan virus, coronavirus, reovirus, cytomegalovirus, and Mycoplasma pulmonis.
- the human myeloma cell line HL-60 (ATCC, CCl-240) was cultured in D-MEM (Gibco, Paisley, UK) complemented with 10% fetal calf serum and Penicillin- Streptomycin.
- the cells were differentiated to granulocytes by culture in presence of 1.25% dimethylsulfoxide (DMSO; Sigma Aldrich Inc., Milwaukee, WI) for six days. Before assaying the cells were washed and resuspended in PBS to a concentration of 10 7 cells/ml.
- DMSO dimethylsulfoxide
- Oxidative burst assay of granulocytes in vitro NADPH activating oils were tested for oxidative burst inducing capacity according to a previously described method (Dahlgren and Karlsson (1999) J Immunol Methods 232: 3-14). In order to get the oils solubilized, they were diluted at 2% concentration in ⁇ -cyclodextrin (Sigma Aldrich) (10 mM in PBS) in PBS. ⁇ - cyclodextrin by itself or the used oil control had no stimulating effect on ROS production.
- ⁇ -cyclodextrin Sigma Aldrich
- the NADPH activators compound 1 (phytol), compound 2 (farnesol) and compound 3 (geranylgeraniol) give strong ROS production from the HL60 cells. These compounds are all non arthritogenic but have arthritis ameliorating effects.
- Pristane is a potent arthritis inducing compound that does not induce ROS production in HL60 cells. Extra-cellular ROS production was measured with an isoluminol assay on HL-60 cells after in vitro stimulation with compound 1 (phytol) ( ⁇ ), compound 2 (farnesol) (•), compound 3 (geranylgeraniol) ( A ) or pristane (O). ( Figure 2).
- Example 4 Compound 1 (phytol) increases oxidative burst in vivo
- compound 1 phytol
- radiolabeled compound 1 phytol
- inguinal lymph nodes, spleen , heart, thymus, kidney, liver, lung, adipose tissue, muscle, injection site tissue and blood were collected in equal amount of saline solution in pre-weight tubes (blood with heparin to prevent coagulation).
- the tissues were homogenized and mixed with ready-safe scintillation liquid (Beckman Coulter, CA).
- Biodistribution was estimated as relative CPM per gram tissue. Besides the large fraction of phytol (> 90%, not shown) that remained as a depot in the injection site, the draining lymph nodes were the primary tissue for accumulation of phytol. The distribution of phytol to the inguinal lymph nodes showed highest accumulation more than one week after injection and showed a decrease after two weeks ( Figure 4). It was at this level determined that phytol was distributed primarily to the cortical regions as well as close to the sinusoidal space of the draining lymph nodes. Moreover, the staining seemed to appear in-between cells or in the cell membrane, i.e. not intracellular.
- PIA Pristane induced arthritis
- s.c. subcutaneous injection at the base of the tail with 200 ⁇ l of pristane .
- Compound 1 (phytol) inhibits development of arthritis.
- a significant preventive effect of compound 1 (phytol) on PIA can be seen in DA.Ncfl DA rats.
- Compound 1 (phytol) was injected s.c. day -5 prior to pristane injection (untreated control ( ⁇ ) and compound 1 (phytol) (A) ). ( Figure 5).
- Pristane induced arthritis was induced in the rats by an subcutaneous (s.c.) injection at the base of the tail with 200 ⁇ l of pristane.
- Therapeutic treatments were administered s.c. or intra peritoneal (Lp.; 200 ⁇ l) after onset of disease in the acute or chronic phase (Figure 6).
- Injection of compound 1 (phytol) ameliorates disease in the acute phase of arthritis ( Figure 6A).
- a significant therapeutic effect of compound 1 (phytol) can be seen in acute phase of PIA in DA.Ncfl D ⁇ rats after two injections (200 ⁇ l) with 5 days in between starting at the estimated peak of disease (day 22).
- Cartilage destruction is decreased after injection of compound 1 (phytol) ( Figure 6B).
- Sera were taken day 38 and analyzed for COMP levels as a measurement of cartilage destruction. Results are presented as circles, where every circle represents one individual and filled circles represent rats with a mean reduction in score after day of first treatment (day 22). Lines represent mean value
- Compound 1 (phytol) decreases arthritis severity in the chronic phase of arthritis ( Figure 6C).
- Compound 1 (phytol) was injected i.p. twice (200 ⁇ l), starting day 70 after pristane injection in DA.Ncfl DA rats with three days between treatments (control ( ⁇ ) and compound 1 (phytol) s.c. (A)).
- the preventive effect of compound 1 (phytol) is not dependent on genetic background (Figure 6D).
- An arthritis preventing effect of compound 1 (phytol) when injected (200 ⁇ l s.c.) 5 days before induction of PIA could also be seen in another arthritis susceptible strain i.e. the Lewis. IF rat, (control ( ⁇ ) and compound 1 (phytol) s.c.
- Compound 1 (phytol) has an arthritis ameliorating effect also in rats with a functional oxidative burst ( Figure 6E). Rats heterozygous for the functional Ncfl (Ncfl E3 ) allele but with an increased arthritis susceptibility locus (Pia3) introduced in the genome on chromosome 6 (Olofsson et al. (2003) Genomics 82: 652-9). Compound 1 (phytol) was injected i.p. (200 ⁇ l) at the estimated peak of disease (control ( ⁇ ) and compound 1 (phytol) (A)).
- Example 8 Compound 1 (phytol) suppresses CIA with oil adjuvant
- Collagen induced arthritis was induced by an s.c. injection of 100 ⁇ l of rat collagen type II (CII; 100 ⁇ g/rat-150 ⁇ g/rat), emulsified in incomplete Freund's adjuvant (IFA; Sigma Aldrich) (Figure 7).
- Compound 1 prevents collagen-induced arthritis in DA.Ncfl DA rats ( Figure 7A). Effect of s.c. administration of phytol (200 ⁇ l) 5 days.
- Example 9 Compound 1 (phytol) suppresses CIA without oil adjuvant
- Non oil collagen induced arthritis was induced by emulsifying rat CII (300 ⁇ g) in a mixture of LPS (50 ⁇ g; Sigma Aldrich), CPG (5'-TCC ATG ACG TTC CTG ACG TT-3'; SEQ ID NO: 1) (45 ⁇ g; MWG-Biotech AG, Ebersberg, Germany) and alum (6 mg; Sigma Aldrich) and injected s.c. in a total volume of 300 ⁇ l.
- LPS 50 ⁇ g; Sigma Aldrich
- CPG 5'-TCC ATG ACG TTC CTG ACG TT-3'; SEQ ID NO: 1
- alum 6 mg; Sigma Aldrich
- Pristane induced arthritis was induced in the rats by a subcutaneous (s.c.) injection at the base of the tail with 150 ⁇ l of pristane.
- Treatments with compound 1 (phytol) or compound 5 (phytyl acetate) were administered to DA.Ncfl D ⁇ rats as 100 ⁇ l subcutaneous injections in the neck at day 8 and 10 after arthritis induction (untreated control (O), compound 1 (phytol) ( ⁇ ) and compound 5 (phytyl acetate) (A)) ( Figure 9).
- Pristane induced arthritis was induced in the rats by a subcutaneous (s.c.) injection at the base of the tail with 150 ⁇ l of pristane.
- Treatments with compound 8 or compound 1 (phytol) were administered to DA.Ncfl DA rats as 100 ⁇ l subcutaneous injections in the neck at day 8 and 10 after arthritis induction, (untreated control (O), compound 1 (phytol) ( ⁇ ) and compound 8 (A)) ( Figure 10).
- Example 12 Arthritis treatment with compound 2 (farnesol) and compound 4 (farnesylacetate)
- Pristane induced arthritis was induced in the rats by a subcutaneous (s.c.) injection at the base of the tail with 150 ⁇ l of pristane.
- Treatments with compound 2 (farnesol) or compound 4 (farnesylacetate) were administered to DA.Ncfl DA rats as 100 ⁇ l subcutaneous injections in the neck at day 8 and 10 after arthritis induction, (untreated control (O), compound 2 (farnesol) ( ⁇ ) and compound 4 (farnesylacetate) (A)) ( Figure 11).
- Example 13 Arthritis treatment with compound 1 (phvtol), compound 6 (di-hydro- phvtol, compound 5 (phytyl acetate), and compound 7 (di-hydro-phytyl acetate
- Pristane induced arthritis was induced in the rats by a subcutaneous (s.c.) injection at the base of the tail with 150 ⁇ l of pristane.
- Treatments with compound 1 (phytol), compound 6 (di-hydro-phytol, compound 5 (phytyl acetate), or compound 7 (di-hydro-phytyl acetate were administered to DA.Ncfl D ⁇ rats as 100 ⁇ l subcutaneous injections in the neck at day 8 and 10 after arthritis induction, (untreated control (O), compound 1 (phytol) ( ⁇ ), compound 6 (di-hydro-phytol ( ⁇ ), compound 5 (phytyl acetate) (A) or compound 7 (di-hydro-phytyl acetate (•)) ( Figure 12).
- Example 14 Arthritis treatment with oral administration of compound 1 (phytol) Pristane induced arthritis (PIA) was induced in the rats by an subcutaneous (s.c.) injection at the base of the tail with 150 ⁇ l of pristane.
- PIA Pristane induced arthritis
- Example 15 Arthritis treatment with oral administration of compound 5 (phytyl acetate)
- Pristane induced arthritis was induced in the rats by an subcutaneous (s.c.) injection at the base of the tail with 150 ⁇ l of pristane.
- Oral treatment with compound 5 (phytyl acetate) was equally effective as oral treatment with compound 1 (phytol) in reducing the severity of arthritis.
- Example 16 Oxidative burst assay of granulocytes in vitro
- the human myeloma cells line HL-60 (ATCC, CCl-240) was cultured in D- MEM (Gibco, Paisley, UK) complemented with 10% fetal calf serum and Penicillin- Streptomycin.
- the cells were differentiated to granulocytes by culture in presence of 1,25% dimethylsulfoxide (DMSO; Sigma Aldrich Inc., Milwaukee, WI) for six days. Before assaying the cells were washed and resuspended in PBS to a concentration of 10 7 cells/ml.
- DMSO dimethylsulfoxide
- NADPH activating oils were tested for oxidative burst inducing capacity according to a previously described method (Dahlgren and Karlsson (1999) J Immunol Methods 232: 3-14). In order to get the oils soluble they were diluted at 2% concentration in ⁇ -cyclodextrin (Sigma Aldrich) (10 mM in PBS) in PBS. ⁇ - cyclodextrin by itself or the used oil control had no stimulating effect on ROS production.
- the NADPH activators compound 1 (phytol), compound 2 (farnesol) and compound 9 (isophytol) give strong ROS production from the HL60 cells. Extracellular ROS production was measured with an isoluminol assay on HL-60 cells after in vitro stimulation with compound 1 (phytol) ( ⁇ ), compound 2 (farnesol) (A) or compound 9 (isophytol) (•) (see Figure 15).
- Example 17 Arthritis treatment by oral gavage with compound 1 (phvtol) at 1.6 or 2.3 g/kg/day
- Pristane induced arthritis was induced in the rats by a subcutaneous (s.c.) injection at the base of the tail with 200 ⁇ l of a 50% mixture of pristane/hexadecane.
- Treatments with compound 1 (phytol) at 1.6 or 2.3 g/kg/day administered to DA.Ncfl D ⁇ rats by oral gavage given by dosing every second day with compound 1 (phytol) 1.6mg/kg/every second day ( ⁇ ), compound 1 (phytol) 3.2 mg/kg/every second day (A) or untreated control (O).
- Fenofibrate (propan-2-yl 2- [4-(4-chlorobenzoyl)phenoxy] -2-methyl-propanoate; Sigma- Aldrich) is known to be an antilipemic agent. It has been suggested that fenofibrate suppresses the development of arthritis by inhibition of NF-kappa B signaling. See, e.g., Okamoto et al. CLIN EXP RHEUMATOL 23 (3): 323-330 MAY- JUN 2005.
- Pristane induced arthritis was induced in the rats by a subcutaneous (s.c.) injection at the base of the tail with 200 ⁇ l of a 50% mixture of pristane/hexadecane.
- Untreated control O.
Abstract
Description
Claims
Priority Applications (5)
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EP07726945A EP2004159A1 (en) | 2006-03-15 | 2007-03-15 | Autoimmune conditions and nadph oxidase defects |
JP2008558825A JP2010521412A (en) | 2006-03-15 | 2007-03-15 | Autoimmune status and NADPH oxidase deficiency |
NZ570803A NZ570803A (en) | 2006-03-15 | 2007-03-15 | Autoimmune conditions and NADPH oxidase defects |
CA002643747A CA2643747A1 (en) | 2006-03-15 | 2007-03-15 | Autoimmune conditions and nadph oxidase defects |
AU2007224438A AU2007224438B2 (en) | 2006-03-15 | 2007-03-15 | Autoimmune conditions and NADPH oxidase defects |
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US78238106P | 2006-03-15 | 2006-03-15 | |
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EP (1) | EP2004159A1 (en) |
JP (1) | JP2010521412A (en) |
KR (1) | KR20090008233A (en) |
CN (1) | CN101404985A (en) |
AU (1) | AU2007224438B2 (en) |
CA (1) | CA2643747A1 (en) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012127214A1 (en) | 2011-03-18 | 2012-09-27 | Pronoxis Ab | Quinolinone derivatives for use in the treatment of an autoimmune disease and/or an inflammatory disease |
EP3000464A3 (en) * | 2014-09-26 | 2016-06-22 | Samsung Electronics Co., Ltd. | Composition comprising farnesol and use thereof |
WO2017044002A1 (en) * | 2015-09-07 | 2017-03-16 | Вагиф Султанович СУЛТАНОВ | Active ingredient of a drug and a drug, a pharmaceutical composition and a method for treating demyelinating diseases of the human body, which includes prophylaxis |
WO2022136952A1 (en) * | 2020-12-23 | 2022-06-30 | Infectious Disease Research Institute | Solanesol vaccine adjuvants and methods of preparing same |
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2007
- 2007-03-15 NZ NZ570803A patent/NZ570803A/en not_active IP Right Cessation
- 2007-03-15 KR KR1020087025212A patent/KR20090008233A/en not_active Application Discontinuation
- 2007-03-15 WO PCT/EP2007/052457 patent/WO2007104790A1/en active Application Filing
- 2007-03-15 EP EP07726945A patent/EP2004159A1/en not_active Withdrawn
- 2007-03-15 CA CA002643747A patent/CA2643747A1/en not_active Abandoned
- 2007-03-15 CN CNA2007800093023A patent/CN101404985A/en active Pending
- 2007-03-15 JP JP2008558825A patent/JP2010521412A/en active Pending
- 2007-03-15 AU AU2007224438A patent/AU2007224438B2/en not_active Ceased
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012127214A1 (en) | 2011-03-18 | 2012-09-27 | Pronoxis Ab | Quinolinone derivatives for use in the treatment of an autoimmune disease and/or an inflammatory disease |
EP3000464A3 (en) * | 2014-09-26 | 2016-06-22 | Samsung Electronics Co., Ltd. | Composition comprising farnesol and use thereof |
US10780061B2 (en) | 2014-09-26 | 2020-09-22 | Daegu Gyeongbuk Institute Of Science And Technology | Composition comprising farnesol and use thereof |
WO2017044002A1 (en) * | 2015-09-07 | 2017-03-16 | Вагиф Султанович СУЛТАНОВ | Active ingredient of a drug and a drug, a pharmaceutical composition and a method for treating demyelinating diseases of the human body, which includes prophylaxis |
RU2631887C2 (en) * | 2015-09-07 | 2017-09-28 | Вагиф Султанович Султанов | Active drug ingredient, drug, pharmaceutical composition and method for treatment of demyelinating diseases of living organism, including disease prevention |
WO2022136952A1 (en) * | 2020-12-23 | 2022-06-30 | Infectious Disease Research Institute | Solanesol vaccine adjuvants and methods of preparing same |
Also Published As
Publication number | Publication date |
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NZ570803A (en) | 2011-06-30 |
CA2643747A1 (en) | 2007-09-20 |
EP2004159A1 (en) | 2008-12-24 |
CN101404985A (en) | 2009-04-08 |
KR20090008233A (en) | 2009-01-21 |
JP2010521412A (en) | 2010-06-24 |
AU2007224438B2 (en) | 2012-07-26 |
AU2007224438A1 (en) | 2007-09-20 |
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