WO2009061906A2 - Traitement des pathologies de mauvais repliement des protéines - Google Patents

Traitement des pathologies de mauvais repliement des protéines Download PDF

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WO2009061906A2
WO2009061906A2 PCT/US2008/082613 US2008082613W WO2009061906A2 WO 2009061906 A2 WO2009061906 A2 WO 2009061906A2 US 2008082613 W US2008082613 W US 2008082613W WO 2009061906 A2 WO2009061906 A2 WO 2009061906A2
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hydrogen
oso
taken together
alkyl
aryl
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PCT/US2008/082613
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WO2009061906A3 (fr
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Christopher B. Eckman
Wing-Cheung Lee
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Mayo Foundation For Medical Education And Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This document relates to methods and materials involved in treating protein misfolding diseases.
  • this document relates to methods and materials involved in using lobeline (e.g., ⁇ -lobeline) and analogs thereof to treat a protein misfolding disease such as Krabbe disease.
  • lobeline e.g., ⁇ -lobeline
  • analogs thereof to treat a protein misfolding disease such as Krabbe disease.
  • Globoid cell leukodystrophy is a lysosomal storage disorder with major neurological manifestations. It is a devastating, autosomal recessive disease that mainly affects infants (about 90 percent of all cases).
  • Krabbe disease is caused by mutations in the galactocerebrosidase (GALC) gene that severely impair its function. In general, less than five percent of normal enzymatic activity is found in patients with GLD. The resulting accumulation of a GALC substrate, psychosine, causes extensive demyelination in both the central and peripheral nervous system.
  • GALC galactocerebrosidase
  • This document provides methods and materials related to treating protein misfolding diseases.
  • this document relates to the use lobeline (e.g., ⁇ - lobeline) and analogs thereof and pharmaceutical composition comprising them, to treat protein misfolding diseases, such as Krabbe disease.
  • lobeline e.g., ⁇ - lobeline
  • pharmaceutical composition comprising them.
  • the methods and materials provided herein can allow clinicians to treat a mammal having a protein misfolding disease, thereby providing the mammal with a longer and healthier quality of life.
  • one aspect of this document features a method for treating a mammal having a protein misfolding disease.
  • the method comprises, or consists essentially of, administering a composition comprising a lobeline compound to the mammal under conditions wherein a symptom of the protein misfolding disease is reduced in severity or eliminated.
  • the protein misfolding disease can be Krabbe disease.
  • the mammal can be a human.
  • the lobeline compound can be ⁇ -lobeline.
  • the composition can comprise two or more lobeline compounds.
  • the method can comprise identifying the mammal as having the protein misfolding disease before the administering step.
  • the method can comprise monitoring the mammal for the reduction in severity or elimination of the symptom after the administering step.
  • this document features a method for treating a protein misfolding disease in a mammal in need thereof.
  • the method comprises, or consists essentially of, administering to the mammal a therapeutically effective amount of a compound of Formula II:
  • R 1 is hydrogen, -OR 10 , -OC(O)N(R 10 XR 11 ), -OC(O)OR 10 , -OC(O)R 10 , -OSO 2 (R 10 ), - OSO 2 N(R 10 XR 11 ), or -OSO 2 (OR 10 ); or R 1 and R 5 taken together form a bond;
  • R 2 is hydrogen, -OR 10 , -OC(O)N(R 10 )(R ⁇ ), -OC(O)OR 10 , -OC(O)R 10 , -OSO 2 (R 10 ), - OSO 2 N(R 10 XR 11 ), or -OSO 2 (OR 10 ); or R 2 and R 6 taken together form a bond;
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R
  • R 14 and R 15 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R 14 and R 15 taken together represent a 5-8 member optionally substituted heterocyclic ring.
  • Each of R 3 and R 4 can be hydrogen.
  • Each of R 1 and R 2 can be hydrogen, -OR 10 , or -OSO 2 (OR 10 ).
  • R 7 can be alkyl.
  • R 1 can be hydrogen, -OR 10 , -OC(O)OR 10 , -OC(O)R 10 , or -
  • R 10 OSO 2 (R 10 ); or R 1 and R 5 taken together can form a bond
  • R 2 can be hydrogen, -OR 10 , or -OSO 2 (R 10 ); or R 2 and R 6 taken together can form a bond
  • R 7 can be alkyl
  • R 10 can be hydrogen, alkyl, aryl, heteroaryl, or heteroaralkyl.
  • the compound of Formula II can have the relative stereochemistry depicted in Formula III:
  • this document features a method for treating a protein misfolding disease in a mammal in need thereof.
  • the method comprises, or consists essentially of, administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:
  • this document features a method for treating a protein misfolding disease in a mammal in need thereof.
  • the method comprises. Or consists essentially of, administering to the mammal a therapeutically effective amount of a compound of Formula IV:
  • this document features the use of a compound in the manufacture of a medicament for the treatment of a protein misfolding disease, wherein the compound has Formula II:
  • R 1 is hydrogen, -OR 10 , - OC(O)N(R 10 XR 11 ), -OC(O)OR 10 , -OC(O)R 10 , -OSO 2 (R 10 ), -OSO 2 N(R 10 XR 11 ), or - OSO 2 (OR 10 ); or R 1 and R 5 taken together form a bond;
  • R 2 is hydrogen, -OR 10 , - OC(O)N(R 10 XR 11 ), -OC(O)OR 10 , -OC(O)R 10 , -OSO 2 (R 10 ), -OSO 2 N(R 10 XR 11 ), or - OSO 2 (OR 10 ); or R 2 and R 6 taken together form a bond;
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
  • Figure 1 is a diagram of a chemical reaction for detecting GALC polypeptide activity.
  • Figure 2 is a graph plotting recombinant GALC polypeptide activity in an in vitro assay containing the indicated amounts of ⁇ LB ( ⁇ M) as a percentage of recombinant GALC polypeptide activity detected in a control reaction lacking ⁇ LB.
  • Figure 3 contains graphs plotting intracellular (lysate) and extracellular (medium) GALC activity in H4-hGALC cells expressing wild-type (WT) or mutant (I546T or D528N) GALC and treated with the indicated amount of ⁇ LB ( ⁇ g/mL). The cells were treated at the indicated concentration of ⁇ LB in a humidified CO 2 incubator at 37 0 C for three days.
  • Figure 4 contains a graph plotting intracellular (lysate) GALC activity in H4- hGALC cells expressing mutant (I546T) GALC and treated with 20 ⁇ g/mL of ⁇ LB.
  • Figure 4 also contains a Western blot analysis of GALC expression in cells treated with or without ⁇ LB.
  • Figure 5 contains a bar graph plotting GALC polypeptide activity detected in human skin fibroblasts obtained from Krabbe patients together with a Western blot analysis of GALC expression in the human skin fibroblasts.
  • the GALC genotype and phenotype of each sample is set forth in Figure 6.
  • Figure 6 contains a table listing the GALC genotype and phenotype of the skin fibroblast samples used in Figure 5.
  • Figure 7 contains chemical structures for various lobeline compounds.
  • Figure 8 contains chemical structures for various lobeline compounds.
  • This document provides methods and materials related to treating a mammal having a protein misfolding disease.
  • this document provides methods and materials related to the use of lobeline (e.g., ⁇ -lobeline) and analogs thereof to treat a protein misfolding disease in a mammal.
  • the methods and materials provided herein can be used to treat a protein misfolding disease in any type of mammal including, without limitation, mice, rats, dogs, cats, horses, cows, pigs, monkeys, and humans.
  • Any type of protein misfolding disease such as Krabbe disease, other leukodystrophies, synucleinopathies, or tauopathies, can be treated using a lobeline compound.
  • symptomatic or asymptomatic Krabbe disease can be treated using a lobeline compound.
  • a protein misfolding disease can be treated by administering a lobeline compound to a mammal having a protein misfolding disease.
  • a single lobeline compound or a combination of lobeline compounds e.g., two, three, four, five, or more lobeline compounds
  • a mammal having a protein misfolding disease can be treated by administering a composition containing ⁇ - lobeline and lobelane to a mammal.
  • the compounds provided herein can be used to treat disease states or conditions related to protein misfolding, e.g., leukodystrophies, synucleinopathies, and tauopathies.
  • leukodystrophies include, but are not limited to metachromatic leukodystrophy, Krabbe disease, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, childhood ataxia with central nervous system hypomyelination (also known as vanishing white matter disease), Alexander disease, Refsum disease, and cerebrotendinous xanthomatosis.
  • tauopathies include, but are not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration (Pick's disease).
  • synucleinopathies include, but are not limited to Parkinson's disease, dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy.
  • cystic fibrosis examples include, but are not limited to cystic fibrosis, marfan syndrome, Fabry disease, Gaucher' s disease, retinitis pigmentosa 3, Alzheimer's disease, Type II diabetes, Parkinson's disease, spongiform encephalopathies such as Creutzfeldt- Jakob disease, primary systemic amyloidosis, secondary systemic amyloidosis, senile systemic amyloidodis, familial amyloid polyneuropathy 1 , hereditary cerebral amyloid angiopathy, hemodialysis-related amyloidosis, familial amyloid polyneuropathy III, Finnish hereditary systemic amyloidosis, medullary carcinoma of the thyroid, atrial amyloidosis, hereditary non- neuropathic systemic amyloidosis, injection- localized amyloidosis, and hereditary renal amyloidosis.
  • cystic fibrosis examples include, but are not limited to cyst
  • lobeline compound such as ⁇ -lobeline can be used to treat a protein misfolding disease.
  • lobeline compounds that can be capable of treating a protein misfolding disease include, without limitation, ⁇ -lobeline, lobelane, lobelanide, those compounds set forth in Figure 7 or 8, and those compounds of Formula I-IV.
  • the lobeline compound can be a compound of Formula I without regard to chirality:
  • R 1 and R 2 can include methylcarbonyl (acetyl), phenylcarbonyl (benzoyl), natural fatty acid groups (e.g., palmitoyl, oleyl, linoleyl, stearyl, and lauryl), and polyethyleneglycol (PEG) covalently bonded to the molecule via a carbonate linkage.
  • R 1 and R 2 can include methylcarbonyl (acetyl), phenylcarbonyl (benzoyl), natural fatty acid groups (e.g., palmitoyl, oleyl, linoleyl, stearyl, and lauryl), and polyethyleneglycol (PEG) covalently bonded to the molecule via a carbonate linkage.
  • PEG polyethyleneglycol
  • each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C1-C30 for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • lower alkyl As used herein, the terms “lower alkyl,” “lower alkenyl,” “lower alkoxy,” and the like, refer to normal, branched, and cyclic hydrocarbyl groups containing one to six carbon atoms.
  • higher alkyl includes alkyl groups containing seven to about 20 carbon atoms.
  • aryl includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • an aryl is estradiol and derivatives thereof.
  • aralkyl refers to an aryl group covalently bonded to an alkyl group.
  • heterocyclyl examples include 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
  • optionally substituted refers to any chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a with a substituent as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like; or has the formula -[(CRSoRSi) n ]Rs 2 , wherein each of R 50 and R 51 independently for each occurrence is hydrogen, alkyl,
  • a lobeline compound provided herein can be converted into a different molecule upon metabolism in a mammal.
  • an acetyl group that is present at R 1 and/or R 2 of a lobeline compound administered to a mammal can be removed by metabolic processes such as those that occur in the gastrointestinal tract or the liver.
  • X can be a methyl group.
  • the chirality at the 2 and 6 positions of the piperidyl ring of a lobeline compound can be the same as in naturally occurring ⁇ -lobeline.
  • R 1 and R 2 can include methylcarbonyl (acetyl), phenylcarbonyl (benzoyl), natural fatty acid groups (e.g., palmitoyl, oleyl, linoleyl, stearyl, and lauryl), and polyethyleneglycol (PEG).
  • methylcarbonyl acetyl
  • phenylcarbonyl benzoyl
  • natural fatty acid groups e.g., palmitoyl, oleyl, linoleyl, stearyl, and lauryl
  • PEG polyethyleneglycol
  • the lobeline compound can be a compound of Formula II:
  • R 1 can be hydrogen, -OR 10 , -OC(O)N(R 10 XR 11 ), -OC(O)OR 10 , -OC(O)R 10 , -
  • R 2 can be hydrogen, -OR 10 , -OC(O)N(R 10 )(R ⁇ ), -OC(O)OR 10 , -OC(O)R 10 , -
  • R 7 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each of R 10 and R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -[C(R 12 ) 2 ]m-R 13 ; or R 10 and R 11 taken together with the nitrogen to which they are bonded represent a 3-10 member optionally substituted heterocyclic ring; R 12 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R 13 independently for each occurrence can be hydrogen -OR 14 , -N(R
  • each of R 3 and R 4 can be hydrogen; and/or each of R 1 and R 2 independently for each occurrence can be hydrogen, -OR 10 , or -OSO 2 (OR 10 ).
  • R 7 can be alkyl.
  • R 1 can be hydrogen, -OR 10 , -OC(O)OR 10 , -OC(O)R 10 , or -
  • R 10 OSO 2 (R 10 ); or R 1 and R 5 taken together can form a bond
  • R 2 can be hydrogen, -OR 10 , or -OSO 2 (R 10 ); or R 2 and R 6 taken together can form a bond
  • R 7 is alkyl
  • R 10 is hydrogen, alkyl, aryl, heteroaryl, or heteroaralkyl.
  • the lobeline compound can have the relative stereochemistry depicted in Formula III:
  • a method for treating a protein misfolding disease in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound selected from the group consisting of:
  • Certain compounds provided herein may exist in particular geometric or stereoisomeric forms. All such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, fall within the scope of this document. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this document.
  • the lobeline compound described herein can have basic functionality. Such basic functionality can exist in free base form or as salt.
  • salts of the lobeline compounds described herein can include hydrochloride, hydrobromide, nitrate, sulfate, tartrate, fumarate, citrate, maleate, ascorbate, lactate, aspartate, mesylate, benzene sulfonate, propionate, or succinate salts.
  • an anionic moiety such as a fatty acid salt (e.g., palmitate salt) can be used.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds provided herein. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound are provided herein in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative pharmaceutically acceptable salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • sulfate bisulfate
  • nitrate acetate
  • valerate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like See, for example, Berg
  • the pharmaceutically acceptable salts of the compounds described herein include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds provided herein can contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
  • ⁇ -lobeline can be chemically synthesized or isolated from a natural source (e.g., Lobelia inflate).
  • the lobeline compounds described herein can be synthesized using numerous methodologies well know in the chemical arts.
  • the secondary hydroxyl of lobeline (Figure 7, Compound 1) can be modified, e.g., by alkylation or acylation, to yield compounds of Formula II where R 1 is -OR 10 , -OC(O)N(R 10 )(R ⁇ ), -OC(O)OR 10 , or - OC(O)R 10 .
  • the hydroxyl group may also be eliminated, e.g., by acid catalyzed elimination or by first forming a leaving group (e.g,, tosylate, bromide, chloride, etc) and reacting the resulting analog with a base, to yield compounds where R 1 and R 5 form a bond (see, e.g., Figure 7, step a).
  • the resulting double bond can be reduced, e.g., using hydrogen/palladium, to yield, for example, lobeline compounds where R 1 , R 3 , and R 5 are hydrogen (see, e.g., Figure 7, step c).
  • Lobeline analogs wherein groups R 2 , R 4 , and R 6 are modified can be accessed via a number of synthetic routes.
  • the free hydroxyl group of lobeline is suitably protected and the ketone is then reduced (see, e.g., Figure 7, step b).
  • the ketone is then reduced (see, e.g., Figure 7, step b).
  • a particular diastereomer is desired, it can either be separated by purification or can be produced using an asymmetric reduction.
  • the resulting alcohol can then be modified as described above to yield the desired analog of lobeline.
  • synthetic chemists can use a broad array of chemical transformations to access other lobeline analogs of interest.
  • Representative examples include palladium coupling reactions to alkenylhalides or aryl halides, oxidations, reductions, reactions with nucleophiles, reactions with electrophiles, pericyclic reactions, installation of protecting groups, removal of protecting groups, and the like.
  • a particular enantiomer of a compound provided herein may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • compositions which comprise a therapeutically effective amount of one or more of the compounds described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; and (2) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic aborption, boluses, powders, granules, pastes for application to the tongue.
  • parenteral administration for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation
  • oral administration for example, drenches (a
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate
  • solubility and bioavailability of the compounds described herein in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound described herein optionally formulated with a poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent
  • compositions described herein include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions described herein suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in- water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3- butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound described herein with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions described herein can be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • Topical administration of the pharmaceutical compositions described herein are useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition can be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions described herein may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • a composition containing a lobeline compound as described herein can be in any appropriate form.
  • a composition described herein can be in the form of a solution or powder with or without a diluent to make an injectable suspension.
  • a composition also can contain additional ingredients including, without limitation, pharmaceutically acceptable vehicles, methyl cellulose, ethanol, various oils such as peanut oil, and dimethyl sulfoxide.
  • a pharmaceutically acceptable vehicle can be, for example, saline, water, lactic acid, and mannitol.
  • the compounds described herein can be administered to a mammalian subject either alone or in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice.
  • the compounds or pharmaceutical compositions can be administered topically, orally, or parenterally.
  • Parenteral administration includes intravenous, intramuscular, intraperitoneal, intrathecal, subcutaneous and transdermal.
  • a combination of lobeline compounds can be administered by different routes.
  • one lobeline compound can be administered orally and a second lobeline compound can be administered via injection.
  • a method for treating a protein misfolding disease comprising contacting a cell with a lobeline compound as provided herein. In certain instances, the contacting occurs in vivo or in vitro.
  • a method for treating a protein misfolding disease comprising contacting a misfolded protein with a lobeline compound.
  • the contacting occurs in vivo or in vitro, e.g., in a mammal.
  • the misfolded protein is a GALC protein.
  • the mammal Before administering a lobeline compound to a mammal, the mammal can be assessed to determine whether or not the mammal has a protein misfolding disease. Any appropriate method can be used to determine whether or not a mammal has a protein misfolding disease.
  • a mammal e.g., human
  • a diagnostic GALC enzyme assay can be used to determine whether or not a mammal has a protein misfolding disease.
  • the mammal can be administered a composition containing a lobeline compound.
  • a composition containing a lobeline compound can be administered to a mammal in any amount, at any frequency, and for any duration effective to achieve a desired outcome (e.g., to reduce a symptom of a protein misfolding disease).
  • a composition containing a lobeline compound can be administered to a mammal having a protein misfolding disease to reduce or eliminate a symptom of a protein misfolding disease 5, 10, 25, 50, 75, 80, 85, 90, 95, or 100 percent.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • an effective amount of a composition containing a lobeline compound can be any amount that reduces the severity of a symptom of a protein misfolding disease without producing significant toxicity to the mammal.
  • an effective amount of a lobeline compound can be from about 0.05 mg/kg to about 100 mg/kg (e.g., from about 0.1 mg/kg to about 50 mg/kg, from about 0.2 mg/kg to about 25 mg/kg, or from about 0.5 mg/kg to about 10 mg/kg).
  • an effective amount of a lobeline compound such as ⁇ -lobeline can be from about 0.01 mg/kg to about 10 mg/kg.
  • the amount of lobeline compound can be increased by, for example, two fold. After receiving this higher concentration, the mammal can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly.
  • the effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal's response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and severity of the protein misfolding disease may require an increase or decrease in the actual effective amount administered.
  • the frequency of administration can be any frequency that reduces the severity of a symptom of a protein misfolding disease without producing significant toxicity to the mammal.
  • the frequency of administration can be from about once a week to about three times a day, or from about twice a month to about six times a day, or from about twice a week to about once a day.
  • the frequency of administration can remain constant or can be variable during the duration of treatment.
  • a course of treatment with a composition containing a lobeline compound can include rest periods.
  • a composition containing a lobeline compound can be administered daily over a two week period followed by a two week rest period, and such a regimen can be repeated multiple times.
  • an effective duration for administering a composition containing a lobeline compound can be any duration that reduces the severity of a symptom of a protein misfolding disease without producing significant toxicity to the mammal.
  • the effective duration can vary from several days to several weeks, months, or years.
  • the effective duration for the treatment of a protein misfolding disease can range in duration from several weeks to several months.
  • an effective duration can be for as long as an individual mammal is alive.
  • Multiple factors can influence the actual effective duration used for a particular treatment.
  • an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, route of administration, and severity of the protein misfolding disease.
  • a course of treatment and the severity of one or more symptoms related to the protein misfolding disease can be monitored. Any method can be used to determine whether or not the severity of a symptom of a protein misfolding disease is reduced.
  • the severity of a symptom of a protein misfolding disease can be assessed by determining GALC activity levels at different time points. The levels of GALC activity determined within tissue at different times can be compared to determine the level of increase of GALC activity following treatment.
  • Example 1 Identifying ⁇ -lobeline as a GALC inhibitor Some human mutations cause protein misfolding of GALC. Expression of the
  • D528N or the L629R GALC mutant in different mammalian cells lines results in rapid turnover of the GALC precursor, protein misprocessing, and reduction in GALC activity.
  • GALC activity from skin fibroblasts of Krabbe disease patients was equal to baseline levels when compared to control cells ( Figure 5, upper panel and Figure 6).
  • Western blot analysis using anti-GALC antibodies revealed lower levels of GALC polypeptide in human skin fibroblasts from Krabbe patients as compared to the levels detected in control cells ( Figure 5, lower panel and Figure 6). Expression of the 28 kDa GALC fragment in all of the mutant fibroblasts isolated from Krabbe disease patients was reduced, suggesting that the lack of GALC polypeptide processing is a characteristic molecular phenotype of the disease.
  • ⁇ -lobeline is a main alkaloid found in the plant Lobelia inflate L.
  • ⁇ LB down-regulated the activity of recombinant GALC by approximately 20 percent at 24 ⁇ M and reached about 32 percent reduction in activity when the concentration was increased to 300 ⁇ M ( Figure 2).
  • H4-hGALC I546T
  • H4-hGALC D528N
  • the ⁇ LB-mediated induction of GALC activity in the I546T mutant corresponds with an increase in processing of the precursor into the 28 kDa GALC fragment as detected using a monoclonal GALC antibody.
  • the results described herein also demonstrate that ⁇ LB can be used to treat protein misfolding disease such as Krabbe disease.

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Abstract

L'invention concerne des procédés et des matériaux associés au traitement d'une pathologie du mauvais repliement des protéines. À titre d'exemple, des procédés et matériaux concernant l'utilisation d'un composé lobéline pour traiter une pathologie de mauvais repliement des protéines sont proposés.
PCT/US2008/082613 2007-11-06 2008-11-06 Traitement des pathologies de mauvais repliement des protéines WO2009061906A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012070008A2 (fr) 2010-11-25 2012-05-31 International Centre For Genetic Engineering And Biotechnology - Icgeb Protéines recombinantes ayant une activité d'inactivation sélective sur des protéines cibles

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087376A (en) * 1997-02-05 2000-07-11 University Of Kentucky Research Foundation Use of lobeline compounds in the treatment of central nervous system diseases and pathologies
US6369052B1 (en) * 2000-08-07 2002-04-09 Georgetown University Combination of huperzine and nicotinic compounds as a neuroprotective agent
US6511992B2 (en) * 1999-05-05 2003-01-28 Les Laboratories Servier Substituted pyridine or piperidine compounds
US20040266824A1 (en) * 1999-07-30 2004-12-30 Crooks Peter A. 2,6-disubstituted piperidines and piperazine compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087376A (en) * 1997-02-05 2000-07-11 University Of Kentucky Research Foundation Use of lobeline compounds in the treatment of central nervous system diseases and pathologies
US6511992B2 (en) * 1999-05-05 2003-01-28 Les Laboratories Servier Substituted pyridine or piperidine compounds
US20040266824A1 (en) * 1999-07-30 2004-12-30 Crooks Peter A. 2,6-disubstituted piperidines and piperazine compounds
US6369052B1 (en) * 2000-08-07 2002-04-09 Georgetown University Combination of huperzine and nicotinic compounds as a neuroprotective agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012070008A2 (fr) 2010-11-25 2012-05-31 International Centre For Genetic Engineering And Biotechnology - Icgeb Protéines recombinantes ayant une activité d'inactivation sélective sur des protéines cibles

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