US20120172429A1 - Permanently charged sodium and calcium channel blockers as anti- inflammatory agents - Google Patents

Permanently charged sodium and calcium channel blockers as anti- inflammatory agents Download PDF

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US20120172429A1
US20120172429A1 US13/382,834 US201013382834A US2012172429A1 US 20120172429 A1 US20120172429 A1 US 20120172429A1 US 201013382834 A US201013382834 A US 201013382834A US 2012172429 A1 US2012172429 A1 US 2012172429A1
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compound
alkyl
alkynyl
alkenyl
heteroalkyl
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Clifford J. Woolf
Bruce P. Bean
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General Hospital Corp
Boston Childrens Hospital
Harvard University
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Definitions

  • the invention provides compounds, methods and kits for the treatment of neurogenic inflammation.
  • the invention features methods and kits for the treatment of neurogenic inflammation by targeting nociceptors with drugs of low molecular weight, while minimizing effects on non-pain-sensing neurons or other types of cells.
  • small, hydrophilic drug molecules gain access to the intracellular compartment of pain-sensing neurons via entry through receptor/channels that are present in pain-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue.
  • Neurogenic inflammation is a mode of inflammation mediated by the efferent (motor) functions of sensory neurons, in which pro-inflammatory mediator molecules released in the periphery by pain-sensing neurons (nociceptors) both activate a variety of inflammatory pathways and also act on the vascular system to alter blood flow and capillary permeability.
  • Neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, exposure to irritants in a variety of tissues, and is thought to play an important role in the pathogenesis of numerous disorders (e.g. migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn).
  • numerous disorders e.g. migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn.
  • One way to reduce neurogenic inflammation is to block excitability in nociceptors, thereby preventing the activation of nociceptor peripheral terminals and the release of pro-inflammatory chemicals.
  • Local anesthetics such as lidocaine and articaine act by inhibiting voltage gated ion channels in neurons.
  • Local anesthetics are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. However, these anesthetics block sodium or calcium channels and thereby the excitability of all neurons, not just pain-sensing neurons.
  • local anesthetics produce unwanted or deleterious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits from block of motor axons and other complications from block of autonomic fibers.
  • Local anesthetics also act on sodium channels on smooth muscle in the cardiovascular and respiratory systems producing deleterious effects.
  • the invention features a method for treating neurogenic inflammation in a patient, such as a human, by administering a therapeutically effective amount of a compound that is capable of entering a nociceptor through a channel-forming receptor present in the nociceptor when the receptor is activated and inhibiting a voltage-gated ion channel present in the nociceptor, wherein the compound does not substantially inhibit said channel when applied to the extracellular face of the channel and when the receptor is not activated.
  • the compound is an inhibitor of voltage-gated sodium channels.
  • Exemplary inhibitors of this class are QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine and pancuronium.
  • the compound is a quarternary amine derivative or other charged derivative of a compound selected from riluzole, mexilitine, phenyloin, carbamazepine, procaine, articaine, bupivicaine, mepivicaine, tocainide, prilocaine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, and fluspirilene.
  • the compound is an inhibitor of calcium channels.
  • Inhibitors of this class include D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, dodecyltrimethylammonium, and terpene compounds (e.g., sesquiterpenes), as well as charged derivatives (e.g., a quarternary amine derivative or a guanylated derivative) of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, or farnesyl amine.
  • Still other exemplary inhibitors of calcium channels can be described by Formulas XI-XIV) and in Tables 1, 2, and 3.
  • the ion channel inhibitor is a charged derivative (e.g., a quarternary amine derivative or a guanylated derivative) of any of compounds (1)-(563). Exemplary derivatives are described herein.
  • the channel-forming receptor can be activated prior to administering the compound by administration of a second compound that opens the channel.
  • the channel-forming receptor can be activated by endogenous compounds present in the patient.
  • the invention also features a kit that includes a composition for treating neurogenic inflammation in a patient and instructions for the administration of the composition to a patient to treat neurogenic inflammation.
  • the composition includes a compound that is capable of entering a nociceptor through a channel-forming receptor present in the nociceptor when the receptor is activated and inhibiting a voltage-gated ion channel present in the nociceptor, wherein the compound does not substantially inhibit said channel when applied to the extracellular face of the channel and when the receptor is not activated.
  • the compound is an inhibitor of voltage-gated sodium channels or calcium channels, such as those described herein.
  • the compound is QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine, pancuronium, or another low molecular weight, charged molecule that inhibits voltage-gated sodium channels when present inside of said nociceptor.
  • the compound is D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium; a quarternary amine derivative, of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, or farnesyl amine; a compound according to any of Formulas (XI), (XII), (XIII-A), (XIII-B), (XIII-C), and (XIV); or a quarternary amine derivative or other charged derivative of any of compounds (1)-(563).
  • compositions, methods, and kits of the invention may optionally feature a second compound that activates the channel-forming receptor.
  • the second compound activates a channel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8.
  • Activators of TRPV1 receptors include but are not limited to capsaicin, eugenol, camphor, clotrimazole, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyl
  • TRPV1 activators include black pepper compounds (e.g., Okumura et al., Biosci Biotechnol Biochem. 74(5):1068-72 (2010) and Riera et al., Br J Pharmacol. 57(8):1398-409 (2009)), terpenoids (Iwasaki et al., Life Sci. 85(1-2)60-69 (2009)), nickel (Luebbert et al., Pflugers Arch.
  • Still other activators of TRPV1 receptors include capsaicinoids and capsaicinoid analogs as described herein (e.g., vanilloids (e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and other capsinoids, capsiconiate, dihydrocapsiconiate and other coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide, N-oleyl-homovanillamide, triprenyl phenols (e.g., s
  • Activators of TRPA1 receptors include but are not limited to cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine
  • TRPA1 activators include: fenamate NSAIDS (Hu et al., Pflugers Arch. 459(4):579-92 (2010)), congeners of AP18 (Defalco et al, Bioorg Med Chem Lett. 20(1):276-9 (2010)), tear gasses CN, CR, and CS (Brône et al., Toxicol Appl Pharmacol.
  • Activators of P2X receptors include but are not limited to ATP, 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate).
  • Activators of TRPM8 receptors include but are not limited to menthol, icilin, eucalyptol, linalool, geraniol, and hydroxycitronellal.
  • the invention features compounds according to Formula (XI),
  • each R 11A , R 11B , and R 11C is selected, independently, from H or C 1-4 alkyl, and where 0, 1, 2, or 3 of the dashed bonds represents a carbon-carbon double bond (i.e., compounds of Formula (XI) can include 0, 1, 2, or 3 double bonds), provided that when 2 or 3 carbon-carbon double bonds are present, the double bonds are not adjacent to one another.
  • compounds of Formula (XI) can be represented by the following formula (XI-A),
  • each R 11A , R 11B , R 11C , and X is according to Formula (XI), and where each dashed bond represents an optional carbon-carbon double bond, or by formula (XI-B),
  • each R 11A , R 11B , R 11C , and X is according to Formula (XI).
  • the compound of Formula (XI) is
  • the invention features compounds according to Formula (XII),
  • each of R 12A , R 12B , R 12C , and R 12D is, independently, selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl; or R 12A and R 12B together complete a heterocyclic ring having at least one nitrogen atom; n is an integer between 1-5; each of R 12E and R 12F is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, or C 3-10 alkheterocyclyl; and X is any pharmaceutically acceptable anion.
  • the compound has the following structure,
  • the invention features a compound having a structure according to one of the following formulas:
  • each R 13A -R 13J and R 13O -R 13T is selected, independently, from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl, OR 13AA , NR 13AB R 13AC , NR 13AD C(O)R 13AE , S(O)R 13AF , SO 2 R 13AG R 13AH , SO 2 NR 13AI R 13AJ , SO 3 R 13AK , CO 2 R 13AL , C(O)R 13AM , and C(O)NR 13AN R 13AO ; each of R 13AA -R 13AO is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; each R 13K , R 13L , R 13M , and
  • the invention features compounds according to the following formula,
  • R 14A is heterocyclyl
  • each of R 14B , R 14C , R 14D , and R1 4E is, independently, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl
  • R 14F is selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl, OR 14G , NR 14H R 14I , NR 14J C(O)R 14K , S(O)R 14L , SO 2 R 14M R 14N , SO 2 NR 14O R 14P , SO 3 R 14Q , CO 2 R 14R
  • the invention also features pharmaceutical compositions that include a compound according to any of Formulas (XI)-(XIV), or any of compounds (1)-(563), and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for oral, nasal, or inhalation administration.
  • the compounds, compositions, methods, and kits of the invention may be used to treat any disorder that is caused, wholly or in part, by neurogenic inflammation.
  • disorders include asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, pancreatitis, chronic cough, sinusisitis (e.g., chronic rhinosinusistis), traumatic brain injury, sepsis (e.g., polymicrobial sepsis), tendinopathies chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants or chemical warfare agents, eczema, cystitis, gastritis, urethritis, migraine headache, psoriasis, rhinitis, rosacea, sunburn, chemical warfare agents, inhaled tear gases, or inhaled pollutants.
  • kits of the invention also feature one or more acetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative agents, or immune modulators.
  • compositions are administered by intraarticular, surgical, intravenous, intramuscular, oral, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intraurethral, intravesicular, intrathecal, epidural, mucosal, aural, or ocular administration by injection, inhalation, or direct contact.
  • the composition is formulated for controlled or sustained release over time.
  • biologically active is meant that a molecule, including biological molecules, such as nucleic acids, peptides, polypeptides, and proteins, exerts a physical or chemical activity on itself or other molecule.
  • a “biologically active” molecule may possess, e.g., enzymatic activity, protein binding activity (e.g., antibody interactions), or cytotoxic activities (e.g., anti-cancer properties).
  • Biologically active agents that can be used in the methods and kits described herein include, without limitation, an antibody or antibody fragment, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.
  • inflammation is meant any types of inflammation, such those caused by the immune system (immune-mediated inflammation) and by the nervous system (neurogenic inflammation), and any symptom of inflammation, including redness, heat, swelling, pain, and/or loss of function.
  • neuroogenic inflammation is meant any type of inflammation mediated by neurons (e.g. nociceptors) or any other component of the central or peripheral nervous system.
  • patient is meant any animal.
  • the patient is a human.
  • Other animals that can be treated using the methods and kits of the invention include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).
  • non-human primates e.g., monkeys, gorillas, chimpanzees
  • domesticated animals e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas
  • companion animals e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds.
  • Compounds useful in the invention include, but are not limited to, those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein.
  • low molecular weight is meant less than about 650 Daltons.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, o
  • alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 4 carbon atoms or C 1-4 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range.
  • an alkyl group from 1 to 4 carbon atoms includes each of C 1 , C 2 , C 3 , and C 4 .
  • a C 1-12 heteroalkyl for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms.
  • Other numbers of atoms and other types of atoms may be indicated in a similar manner.
  • alkyl and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive.
  • Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • C 1-4 alkyl is meant a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms.
  • a C 1-4 alkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 1-4 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.
  • C 2-4 alkenyl is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 4 carbon atoms.
  • a C 2-4 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members.
  • the C 2-4 alkenyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2-4 alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.
  • C 2-4 alkynyl is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 4 carbon atoms.
  • a C 2-4 alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the C 2-4 alkynyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2-4 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • C 2-6 heterocyclyl is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom.
  • a nitrogen atom in the heterocycle may optionally be quaternized.
  • Heterocycles include, without limitation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carboliny
  • Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl.
  • Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
  • C 6-12 aryl is meant an aromatic group having a ring system comprised of carbon atoms with conjugated ⁇ electrons (e.g., phenyl).
  • the aryl group has from 6 to 12 carbon atoms.
  • Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the aryl group may be substituted or unsubstituted.
  • substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
  • C 7-14 alkaryl is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
  • aryl group e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl
  • C 3-10 alkcycloalkyl is meant an alkyl substituted by a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl) having from 3-10 carbon atoms.
  • a cycloalkyl group e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl
  • C 3-10 alkheterocyclyl is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).
  • C 1-7 heteroalkyl is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P.
  • Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides.
  • a heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members.
  • the heteroalkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • Examples of C 1-7 heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.
  • halide is meant bromine, chlorine, iodine, or fluorine.
  • fluoroalkyl is meant an alkyl group that is substituted with a fluorine atom.
  • perfluoroalkyl is meant an alkyl group consisting of only carbon and fluorine atoms.
  • Carboxyalkyl is meant a chemical moiety with the formula —(R)—COOH, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
  • hydroxyalkyl is meant a chemical moiety with the formula —(R)—OH, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
  • alkoxy is meant a chemical substituent of the formula —OR, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
  • aryloxy is meant a chemical substituent of the formula —OR, wherein R is a C 6-12 aryl group.
  • alkylthio is meant a chemical substituent of the formula —SR, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
  • arylthio is meant a chemical substituent of the formula —SR, wherein R is a C 6-12 aryl group.
  • quaternary amino is meant a chemical substituent of the formula —(R)—N(R′)(R′′)(R′′′) + , wherein R, R′, R′′, and R′′′ are each independently an optionally substituted alkyl, heteroalkyl, alkaryl, alkcycloalkyl, alkheterocyclyl, alkenyl, alkynyl, heteroaryl, or aryl group as described herein. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety.
  • the nitrogen atom, N is covalently attached to four carbon atoms of the alkyl, heteroalkyl, alkaryl, alkcycloalkyl, alkheterocyclyl, alkenyl, alkynyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom.
  • charged moiety is meant a moiety which gains a proton at physiological pH thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium) or a moiety that includes a net formal positive charge without protonation (e.g., quaternary ammonium).
  • the charged moiety may be either permanently charged or transiently charged.
  • the term “parent” refers to a channel blocking compound which can be modified by quaternization or guanylation of an amine nitrogen atom present in the parent compound.
  • the quaternized and guanylated compounds are derivatives of the parent compound.
  • the guanidyl derivatives described herein are presented in their uncharged base form. These compounds can be administered either as a salt (i.e., an acid addition salt) or in their uncharged base form, which undergoes protonation in situ to form a charged moiety.
  • terapéuticaally effective amount means an amount sufficient to produce a desired result, for example, the reduction or elimination of neurogenic inflammation in a patient (e.g., a human) suffering from a condition, disease, or illness that is caused wholly or in part by neurogenic inflammation (e.g. asthma, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis, rosacea, or sunburn).
  • a patient e.g., a human suffering from a condition, disease, or illness that is caused wholly or in part by neurogenic inflammation (e.g. asthma, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis, rosacea, or sunburn).
  • neurogenic inflammation e.g. asthma, arthritis, colitis, contact dermatitis, diabetes, e
  • FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg/kg) on the edema elicited by injection of complete Freund's adjuvant (CFA) in the rat hindpaw determined by measuring the total volume of the hindpaw by plethysmography.
  • CFA complete Freund's adjuvant
  • the degree of swelling produced by injection of CFA is reduced by administration of QX-314 reflecting reduction in neurogenic edema resulting from the blockade of nociceptors by QX314.
  • QX-314 by itself has no effect different from administration of saline.
  • FIG. 2 shows the inhibition of voltage-dependent calcium channel current in a dorsal root ganglion (DRG) neuron by N-methyl-verapamil applied in the presence of capsaicin to open TRPV1 channels. Entry of the drug into the cell, and its blocking action, depends on applying the drug in the presence of capsaicin to activate the TRPV1 channels present in the neuronal membrane.
  • DRG dorsal root ganglion
  • the present invention features methods and kits for the treatment of neurogenic inflammation by administering a positively-charged, voltage-gated ion channel inhibitor.
  • a positively-charged, voltage-gated ion channel inhibitor is administered alone or in combination with a TRP channel agonist such as capsaicinoid (e.g.
  • a “caine” drug e.g., amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or trimecaine).
  • a “caine” drug e.g., amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimet
  • Voltage-gated ion channels in pain-sensing neurons are currently of great interest in developing strategies to treat neurogenic inflammation.
  • Blocking voltage-dependent sodium channels in nociceptors can reduce or eliminate neurogenic inflammation by preventing activation of nociceptor peripheral terminals and the release of pro-inflammatory chemicals.
  • a limitation in designing small organic molecules that inhibit sodium channels or calcium channels is that they must be active when applied externally to the target cell. The vast majority of such externally-applied molecules are hydrophobic and can pass through cell membranes. Accordingly, such molecules will enter all cells and thus exhibit no selectivity for affecting only nociceptors.
  • TRP channels transient receptor potential ion channel
  • TRP channels e.g., TRPAV1, TRPA1, TRPM8, and P2X(2/3)
  • TRP channels in nociceptors are not active but require a noxious thermal, mechanical, or chemical stimulus to activate them.
  • TRP channels in nociceptors can be activated by an exogenous TRP ligand (i.e. TRP agonist) such as capsaicin, which opens the TRPV1 channel.
  • TRP ligand i.e. TRP agonist
  • one approach to selectively targeting nociceptors is to co-administer the membrane-impermeant ion channel inhibitor with an exogenous TRP ligand that permits passage of the inhibitor through the TRP channel into the cell.
  • the exogenous TRP ligand can also be another capsaicinoid, mustard oil, or lidocaine.
  • TRP channels may be active in response to exogenous irritant activators such as inhaled acrolein from smoke or chemical warfare agents such as tear gas.
  • TRP channels can be activated in the absence of exogenous TRP activators/ligands by endogenous inflammatory activators that are generated by tissue damage, infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cell activation, immune mediator production, and oxidative stress.
  • endogenous molecules e.g., protons, lipids, and reactive oxygen species
  • TRP channels expressed on nociceptors, allowing membrane-impermeant, voltage-gated ion channel blockers to gain access to the inside of the nociceptor through the endogenously-activated TRP channels.
  • Endogenous inflammatory activators of TRP channels include, for example, prostaglandins, nitric oxide (NO), peroxide (H 2 O 2 ), cysteine-reactive inflammatory mediators like 4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin).
  • IL-1 interleukin 1
  • NEF nerve growth factor
  • bradykinin bradykinin
  • membrane-impermeant, positively-charged inhibitors of voltage-gated ion channels e.g., quarternary ammonium derivatives, such as QX-314
  • QX-314 quarternary ammonium derivatives, such as QX-314
  • an exogenous TRP ligand can be used to selectively target nociceptors in order to effectively treat (e.g., eliminate or alleviate) neurogenic inflammation in a patient (e.g., a human).
  • Inflammation is a complex set of responses to harmful stimuli that results in localized redness, swelling, and pain. Inflammation has two components, one driven by antigens and mediated by immune cells (immune-mediated inflammation) and one mediated by the nervous system (neurogenic inflammation). Neurogenic inflammation results from the efferent functions of pain-sensing neurons (nociceptors), wherein neuropeptides and other chemicals that are pro-inflammatory mediators are released from the peripheral terminals of the nociceptors when they are activated.
  • nociceptors pain-sensing neurons
  • This release process is mediated by calcium influx and exocytosis of vesicles, and the pro-inflammatory mediators include substance P, neurokinin A and B (collectively known as tachykinins), and calcitonin gene-related peptide (CGRP).
  • substance P substance P
  • neurokinin A and B collectively known as tachykinins
  • CGRP calcitonin gene-related peptide
  • peripheral terminal chemicals stimulate a variety of inflammatory responses.
  • substance P can result in an increase in capillary permeability such that plasma proteins leak from the intravascular compartment into the extracellular space (plasma extravasation), causing edema. This can be detected as a wheal (a firm, elevated swelling of the skin) which is one component of a triad of inflammatory responses—wheal, red spot, and flare—known as the Lewis triple response.
  • wheal a firm, elevated swelling of the skin
  • flare a flare
  • the release of CGRP causes vasodilation, leading to increased blood flow. This can be detected as a flare, which is another component of the Lewis triple response.
  • Substance P also has a pro-inflammatory action on immune cells (e.g. macrophages, T-cells, mast cells, and dendritic cells) via their neurokinin-1 (NK1) receptor.
  • immune cells e.g. macrophages, T-cells, mast cells, and dendritic cells
  • NK1 receptor neurokinin-1 receptor
  • efferent functions of nociceptors can be triggered by: 1) Direct activation of a nociceptor terminal by a peripheral adequate stimulus applied to the terminal (e.g. a pinch); 2) Indirect antidromic activation of a non-stimulated nociceptor terminal by the axon reflex, wherein action potential input from one terminal of a nociceptor, upon reaching a converging axonal branch point in the periphery, results in an action potential traveling from the branch point down to the peripheral terminal of a non-stimulated terminal; and 3) Activation as a result of activity in nociceptor central terminals in the CNS traveling to the periphery (e.g., primary afferent depolarization of central terminals produced by GABA can be sufficient to initiate action potentials traveling the “wrong way”).
  • Activation as a result of activity in nociceptor central terminals in the CNS traveling to the periphery e.g., primary afferent depolarization of central
  • neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, and exposure to irritants in soft tissue, skin, the respiratory system, joints, the urogenital and GI tract, the liver, and the brain.
  • Neurogenic inflammatory disorders include asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis, rosacea, and sunburn, pancreatitis, chronic cough, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, or chemical warfare agents, as described herein.
  • Asthma is a chronic respiratory disorder that is characterized by airway obstruction, bronchial hyperresponsiveness, and bronchial inflammation. Asthma can be induced by a variety of stimuli, including natural inhaled allergens (e.g. dust mites, pollen, and mold), household organic compounds (e.g. soap, perfume, shampoo, creams, and lotions), medications, industrial chemicals, food allergies, exercise, hormonal changes, and psychological stress. Patients who chronically suffer from asthma experience episodes of hypersensitivity to such stimuli where the bronchi contract in spasms. During an asthma episode, inflammation of the airways causes bronchoconstriction and excess mucus production, making it difficult for the patient to breathe.
  • natural inhaled allergens e.g. dust mites, pollen, and mold
  • household organic compounds e.g. soap, perfume, shampoo, creams, and lotions
  • medications e.g. soap, perfume, shampoo, creams, and lotions
  • industrial chemicals e.g. soap, perfume, shampoo
  • TRPV1 and TRPA1 channels also contribute to the neurogenic component of allergic asthma as well as cough and rhinitis.
  • Arthritis is a group of conditions involving inflammation and damage to the joints of the body. Arthritis can have many causes, including physical trauma and aging (osteoarthritis), autoimmune disease (rheumatoid arthritis and psoriatic arthritis), infection (septic arthritis), and gout (gouty arthritis).
  • RA Rheumatoid arthritis
  • synermal arthritis is a chronic, systemic inflammatory disorder that principally affects the joints (synovitis), characterized by destruction of articular cartilage and bending/stiffness of the joints (ankylosis), and which leads to pain and substantial loss of mobility.
  • RA can also cause inflammation in the skin, lungs, and kidneys.
  • Colitis is a group of chronic autoimmune disorders characterized by inflammation of the colon. Symptoms of colitis include pain, tenderness of the abdomen, fatigue, rapid weight loss, ulcers (ulcerative colitis), and gastrointestinal bleeding. Colitis can also be triggered by many foods, including alcohol, caffeine, dairy products, spicy foods, nuts, seeds, meats, refined sugar, and raw vegetables. It is known that neurogenic mechanisms are important to the inflammatory processes in colitis. For example, studies have shown that induced colitis inflammation in mice can be mitigated using NK-1 and CGRP receptor antagonists. (Nguyen et al. Canadian J. Phys. Pharm. 81:920, 2003.)
  • Contact dermatitis is the local irritation of superficial regions of the skin caused by contact with irritants or allergens.
  • the most common causes of allergic contact dermatitis are plants such as poison ivy and poison oak.
  • Common causes of irritant contact dermatitis are chemicals such as harsh soaps, detergents, and cleaning products. Symptoms of contact dermatitis include rash, blisters, wheals, hives, and burning itch.
  • the role of neurogenic inflammation in contact dermatitis has been discussed, for example, in Guy, AMA Arch. Derm. Syphilol. 66:1, 1952.
  • Gastritis refers to a collection of disorders which induce inflammation of the stomach lining. Gastritis can be caused by excessive alcohol consumption, prolonged use of NSAIDs such as aspirin or ibuprofen, and chronic infection by bacteria (primarily Helicobacter pylori ). Certain autoimmune disorders can also cause gastritis. Symptoms include internal bleeding, pain (especially in the upper abdomen), vomiting, and bloating. Gastritis can also lead to increased risk of stomach cancer.
  • Migraine is a neurological disorder, more common in women than in men, that is characterized by headache, nausea, and altered perception. Migraine proceeds in several phases: 1) a prodrome phase that includes fatigue, food craving, neck stiffness, altered mood, and constipation or diarrhea; 2) an aura phase that includes disturbances of vision consisting of white/multicolored flashes of lights or dazzling lines, feelings of “pins-and-needles” in the hand and arm, auditory/olfactory hallucinations, vertigo, tingling/numbness of the face, and hypersensitivity to touch; 3) a pain phase that includes a throbbing headache accompanied by nausea, vomiting, blurred vision, nasal stuffiness, diarrhea, and local edema; and 4) a postdrome phase including fatigue and feelings of “hangover.”
  • a prodrome phase that includes fatigue, food craving, neck stiffness, altered mood, and constipation or diarrhea
  • an aura phase that includes disturbances of vision consisting of white/multicolored flashes of lights or dazzling
  • Rhinitis known commonly as the running nose, is a disorder involving irritation and inflammation of internal nasal mucous membranes. Rhinitis is characterized by the generation of large amounts of mucus, producing running nose, nasal congestion, and post-nasal drip. According to recent estimates, more than 50 million people in the U.S. alone suffer from rhinitis yearly. Rhinitis is laked into infective rhinitis (caused by bacterial infection), nonallergic rhinitis (caused by hormones, drugs, and foods), and allergic rhinitis (caused by immune reactions to allergens, e.g. hayfever). The role of neurogenic inflammation in the pathogenesis of rhinitis is similar to that of asthma, where environmental substances enhance the immune response, leading to downstream release of substance P from neurons.
  • Cystitis is inflammation of the urinary bladder.
  • cystitis There are several types of cystitis, including traumatic cystitis, interstitial cystitis, eosinophilic cystitis, radiation cystitis, and hemorrhagic cystitis.
  • Interstitial cystitis also known as painful bladder syndrome, is a disorder characterized by urination pain, urinary frequency, urgency, and pressure in the bladder.
  • traumatic cystitis interstitial cystitis has not been shown to be caused by bacterial infection. The cause of interstitial cystitis is unknown but has been proposed to involve neurogenic inflammation.
  • Additional neurogenic inflammatory disorders will be known to those skilled in the art, and include, but are not limited to sunburn, inflammatory conditions with a neurogenic component such as inflammation of blood vessels, eczema, rosacea, psoriasis, gingivitis, pancreatitis, chronic cough, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies chronic urticaria, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, or chemical warfare agents.
  • a neurogenic component such as inflammation of blood vessels, eczema, rosacea, psoriasis, gingivitis, pancreatitis, chronic cough, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies chronic urticaria, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, or chemical warfare agents.
  • Inhibitors of voltage-gated ion channels that are suitable for use in the methods and kits of the invention for the treatment of neurogenic inflammation are desirably positively-charged, hydrophilic compounds.
  • the compounds are permanently charged (i.e., have a charge that is not transient).
  • the compounds are transiently charged.
  • Suitable inhibitors of voltage-gated sodium channels include, but are not limited to, QX-314, N-methyl-procaine (QX-222), N-octyl-guanidine, 9-aminoacridine, and pancuronium.
  • Suitable inhibitors of voltage-gated calcium channels include, but are not limited to, D-890 (quaternary methoxyverapamil), CERM 11888 (quaternary bepridil), N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, dodecyltrimethylammonium, and other compounds as described herein (see, e.g., charged derivatives of the compounds described in Tables 1 and 2).
  • inhibitors of voltage-gated ion channels that would be of a suitable size to be useful in the methods of the invention (e.g., from about 100 to 4,000 Da, 100 to 3,000 Da, 100 to 2,000 Da, 150 to 1,500 Da, or even 200 to 1,200 Da) and that have amine groups, or can be modified to contain amine groups, that can be readily modified to be charged (e.g., as positively-charged quarternary amines, or as transiently charged, e.g., guanylated, compounds).
  • Such inhibitors include, but are not limited to, riluzole, mexilitine, phenyloin, carbamazepine, procaine, tocainide, prilocaine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, articaine, bupivicaine, mepivicaine, and fluspirilene.
  • Compounds that can be used in the methods and kits of the invention for the treatment of inflammation include compounds of formulas I-X, below.
  • each of R 1A , R 1B , and R 1C is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR 1H , NR 1I R 1J , NR 1K C(O)R 1L , S(O)R 1M , SO 2 R 1N R 1O , SO 2 NR 1P R 1Q , SO 3 R 1R , CO 2 R 1S , C(O)R 1T , and C(O)NR 1U R 1V ; and each of R 1H , R 1I , R 1K , R 1L , R 1M , R 1N , R 1O , R 1P , R 1Q , R 1R , R 1S , R 1T , R 1U , and R 1V is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C
  • X 1 is —NHC(O)—.
  • exemplary compounds of formula I include methylated quaternary ammonium derivatives of anesthetic drugs, such as N-methyl lidocaine, N,N-dimethyl prilocaine, N,N,N-trimethyl tocainide, N-methyl etidocaine, N-methyl ropivacaine, N-methyl bupivacaine, N-methyl levobupivacaine, N-methyl mepivacaine. These derivatives can be prepared using methods analogous to those described in Scheme 1.
  • Compounds of formula I include QX-314 (CAS 21306-56-9) and QX-222 (CAS 21236-55-5) (below).
  • each of R 2A , R 2B , and R 2C is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR 2I , NR 2J R 2K , NR 2L C(O)R 2M , S(O)R 2N , SO 2 R 2O R 2P , SO 2 NR 2Q R 2R , SO 3 R 2S , CO 2 R 2T , C(O)R 2U , and C(O)NR 2V R 2W ; and each of R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O , R 2P , R 2Q , R 2R , R 2S , R 2T , R 2U , R 2V , R 2W is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR
  • R 2H is H or CH 3 .
  • R 2F and R 2G combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
  • X 2 is —NHC(O)—.
  • Exemplary compounds of formula II include N-guanidyl derivatives (e.g., —C(NH)NH 2 derivatives) of anesthetic drugs, such as desethyl-N-guanidyl lidocaine, N-guanidyl prilocaine, N-guanidyl tocainide, desethyl-N-guanidyl etidocaine, desbutyl-N-guanidyl ropivacaine, desbutyl-N-guanidyl bupivacaine, desbutyl-N-guanidyl levobupivacaine, desmethyl-N-guanidyl mepivacaine.
  • anesthetic drugs such as desethyl-N-guanidyl lidocaine, N-guanidyl prilocaine, N-guanidyl tocainide, desethyl-N-guanidyl etidocaine, desbutyl-N
  • guanidyl derivatives described herein are presented in their uncharged base form. These compounds can be administered either as a salt (i.e., an acid addition salt) or in their uncharged base form, which undergoes protonation in situ to form a charged moiety.
  • each of R 3A , R 3B , and R 3C is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, OR 3L , NR 3M R 3N , NR 3O C(O)R 3P , S(O)R 3Q , SO 2 R 3R R 3S , SO 2 NR 3T R 3U , SO 3 R 3V , CO 2 R 3W , C(O)R 3X , and C(O)NR 3Y R 3Z ; and each of R 3L , R 3M , R 3N , R 3O , R 3P , R 3Q , R 3R , R 3S , R 3T , R 3U , R 3V , R 3W , R 3X , R 3Y , R 3Z is
  • the quaternary nitrogen in formula III is identified herein as N′.
  • exemplary compounds of formula III include methylated quaternary ammonium derivatives of anesthetic drugs, such as N′-methyl procaine, N′-methyl proparacaine, N′-methyl allocain, N′-methyl encainide, N′-methyl procainamide, N′-methyl metoclopramide, N′-methyl stovaine, N′-methyl propoxycaine, N′-methyl chloroprocaine, N′,N′-dimethyl flecainide, and N′-methyl tetracaine.
  • anesthetic drugs such as N′-methyl procaine, N′-methyl proparacaine, N′-methyl allocain, N′-methyl encainide, N′-methyl procainamide, N′-methyl metoclopramide, N′-methyl stovaine, N′-methyl propoxycaine, N′-methyl chloroprocaine, N′,
  • each of R 4A and R 4B is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, OR 4L , NR 4M R 4N , NR 4O C(O)R 4P , S(O)R 4Q , SO 2 R 4R R 4S SO 2 NR 4T R 4U , SO 3 R 4V , CO 2 R 4W , C(O)R 4X , and C(O)NR 4Y R 4Z ; and each of R 4L , R 4M R 4N , R 4O , R 4P , R 4Q , R 4R , R 4S , R 4T , R 4U , R 4V , R 4W , R 4X , R 4Y , and R 4Z is independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hetero
  • the quaternary nitrogen in formula IV is identified herein as N′′.
  • exemplary compounds of formula III include methylated quaternary ammonium derivatives of anesthetic drugs, such as N′′,N′′,N′′-trimethyl procaine, N′′,N′′,N′′-trimethyl proparacaine, N′′,N′′,N′′-trimethyl procainamide, N′′,N′′,N′′-trimethyl metoclopramide, N′′,N′′,N′′-trimethyl propoxycaine, N′′,N′′,N′′-trimethyl chloroprocaine, N′′,N′′-dimethyl tetracaine, N′′,N′′,N′′-trimethyl benzocaine, and N′′,N′′,N′′-trimethyl butamben.
  • These derivatives can be prepared using methods analogous to those described in Scheme 1.
  • each of R 5A , R 5B , and R 5C is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, OR 5M , NR 5N R 5O , NR 5P C(O)R 5Q , S(O)R 5R , SO 2 R 5S R 5T , SO 2 NR 5U R 5V , SO 3 R 5W , CO 2 R 5X , C(O)R 5Y , and C(O)NR 5Z R 5AA ; and each of R 5M , R 5N , R 5O , R 5P , R 5Q , R 5R , R 5S , R 5T , R 5U , R 5V , R 5W , R 5X , R 5Y , R 5Z , and R 5AA
  • R 5L is H or CH 3 .
  • R 5J and R 5K combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
  • the guanylated nitrogen in formula V is identified herein as N′.
  • Exemplary compounds of formula V include N-guanidyl derivatives (e.g., —C(NH)NH 2 derivatives) of anesthetic drugs, such as such as desethyl-N′-guanidyl procaine, desethyl-N′-guanidyl proparacaine, desethyl-N′-guanidyl allocain, desmethyl-N′-guanidyl encainide, desethyl-N′-guanidyl procainamide, desethyl-N′-guanidyl metoclopramide, desmethyl-N′-guanidyl stovaine, desethyl-N′-guanidyl propoxycaine, desethyl-N′-guanidyl chloroprocaine, N′-guanidyl flecainide, and desethyl-N′-guanidyl tetracaine.
  • anesthetic drugs
  • each of R 6A and R 6B is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, OR 6K , NR 6L R 6M , NR 6N C(O)R 6O , S(O)R 6P , SO 2 R 6Q R 6R , SO 2 NR 6S R 6T , SO 3 R 6U , CO 2 R 6V , C(O)R 6W , and C(O)NR 6X R 6Y ; and each of R 6K , R 6L , R 6M , R 6N , R 6O , R 6P , R 6Q , R 6R , R 6S , R 6T , R 6U , R 6V , R 6W , R 6X , and R 6Y is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 al
  • R 6J is H or CH 3 .
  • R 6H and R 6I combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
  • the guanylated nitrogen in formula V is identified herein as N′′.
  • Exemplary compounds of formula VI include N-guanidyl derivatives (e.g., —C(NH)NH 2 derivatives) of anesthetic drugs, such as such as N′′-guanidyl procaine, N′′-guanidyl proparacaine, N′′-guanidyl procainamide, N′′-guanidyl metoclopramide, N′′-guanidyl propoxycaine, N′′-guanidyl chloroprocaine, N′′-guanidyl tetracaine, N′′-guanidyl benzocaine, and N′′-guanidyl butamben.
  • anesthetic drugs such as such as N′′-guanidyl procaine, N′′-guanidyl proparacaine, N′′-guanidyl procainamide, N′′-guanidyl metoclopramide, N′′-guanidyl propoxycaine, N′′-guanidyl chloroproca
  • each of R 7A , R 7B , and R 7C is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, OR 7L , NR 7M R 7N , NR 7O C(O)R 7P , S(O)R 7Q , SO 2 R 7R R 7S , SO 2 NR 7T R 7U , SO 3 R 7V , CO 2 R 7W , C(O)R 7X , and C(O)NR 7Y R 7Z ; and each of R 7L , R 7M , R 7N , R 7O , R 7P , R 7Q , R 7R , R 7S , R 7T , R 7U , R 7V , R 7W , R 7X , R 7Y , and R 7Z
  • X 7 is —C(O)NH—.
  • exemplary compounds of formula VII include methylated quaternary ammonium derivatives of anesthetic drugs, such as N′-methyl dibucaine. These derivatives can be prepared using methods analogous to those described in Scheme 1.
  • each of R 8A , R 8B , and R 8C is, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, OR 8L , NR 8M R 8N , NR 8O C(O)R 8P , S(O)R 8Q , SO 2 R 8R R 8S , SO 2 NR 8T R 8U , SO 3 R 8V , CO 2 R 8W , C(O)R 8X , and C(O)NR 8Y R 8Z ; and each of R 8L , R 8M , R 8N , R 8O , R 8P , R 8Q , R 8R , R 8S , R 8T , R 8U , R 8V , R 8W , R 8X , R 8Y , and R 8Z
  • R 8AA , R 8AB , and R 8AD is independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; each of R 8D , R 8E , R 8F , and R 8G is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, and C 3-10 alkheterocyclyl; R 8H is H or C 1-4 alkyl; and each of R 8I , R 8J , and R 8K is
  • R 8K is H or CH 3 .
  • R 8I and R 8J combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
  • the guanylated nitrogen in formula V is identified herein as N′.
  • X 8 is —C(O)NH—.
  • Exemplary compounds of formula VIII include N-guanidyl derivatives (e.g., —C(NH)NH 2 derivatives) of anesthetic drugs, such as such as desethyl-N-guanidyl dibucaine. These derivatives can be prepared using methods analogous to those described in Schemes 2-5.
  • each of R 9A , R 9B , R 9C , R 9D , and R 9E is independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR 9I , NR 9J R 9K , NR 9L C(O)R 9M , S(O)R 9N , SO 2 R 9O R 9P , SO 2 NR 9Q R 9R , SO 3 R 9S , CO 2 R 9T , C(O)R 9U , and C(O)NR 9V R 9W ; and each of R 9I , R 9J , R 9K , R 9L , R 9M , R 9N , R 9O , R 9P , R 9Q , R 9R , R 9S , R 9T , R 9U , R 9V , and R 9W is, independently, selected from H, C 1-4 alky
  • each of R 9F , R 9G , and R 9H is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, or R 9F and R 9G together complete a heterocyclic ring having two nitrogen atoms.
  • R 9F and R 9G form a heterocyclic ring having two nitrogen atoms
  • the resulting guanidine group is, desirably, selected from
  • R 9H is H or CH 3 .
  • R 9F and R 9G combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
  • Exemplary compounds of formula IX include N-guanidyl derivatives (e.g., —C(NH)NH 2 derivatives), such as N-guanidyl fluoxetine, and methylated quaternary ammonium derivatives, such as N,N-dimethyl fluoxetine. These derivatives can be prepared using methods analogous to those described in Schemes 1-5.
  • W 3 is O, NH, NCH 2 R 10J , NC(O)CH 2 R 10J , CHCH 2 R 10J , C ⁇ CHR 10J , or C ⁇ CHR 10K ;
  • W 1 -W 2 is S, O, OCHR 10K , SCHR 10K , N ⁇ CR 10K , CHR 10L —CHR 10K , or CR 10L ⁇ CR 10K ;
  • each of R 10A , R 10B , R 10C , R 10D , R 10E , R 10F , R 10G , and R 10H is, independently, selected from H, OH, halide, C 1-4 alkyl, and C 2-4 heteroalkyl;
  • R 10J is CH 2 CH 2 X 10A or CH(CH 3 )CH 2 X 10A ;
  • R 10L is H or OH;
  • R 10K is H, OH, or the group:
  • X 10A is NR 10M R 10N R 10P , or NR 10Q X 10C ;
  • X 10B is NR 10R R 10S , or NX 10C ; each of R 10M , R 10N , R 10P , R 10R , and R 10S is, independently, selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl, or R 10R , and R 10S together complete a heterocyclic ring having at least one nitrogen atom;
  • R 10Q is H or C 1-4 alkyl;
  • X 10C is
  • each of R 10T , R 10U , and R 10V is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, or R 10T and R 10V together complete a heterocyclic ring having two nitrogen atoms.
  • R 10T and R 10V form a heterocyclic ring having two nitrogen atoms
  • the resulting guanidine group is, desirably, selected from
  • R 10U is H or CH 3 .
  • R 10T and R 10V combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
  • Exemplary compounds of formula X include N-guanidyl derivatives (e.g., —C(NH)NH 2 derivatives) and methylated quaternary ammonium derivatives.
  • N-guanidyl derivatives of formula X include, without limitation, N-guanidyl amoxapine, desmethyl-N-guanidyl trimipramine, desmethyl-N-guanidyl dothiepin, desmethyl-N-guanidyl doxepin, desmethyl-N-guanidyl amitriptyline, N-guanidyl protriptyline, N-guanidyl desipramine, desmethyl-N-guanidyl clomipramine, desmethyl-N-guanidyl clozapine, desmethyl-N-guanidyl loxapine, N-guanidyl nortriptyline, desmethyl-N-guanidyl cyclobenzaprine, desmethyl-N-guanidyl cyproheptadine, desmethyl-N-guanidyl olopatadine, desmethyl-N-guanidyl promethazine, desmethyl-
  • Methylated quaternary ammonium derivatives of formula X include, without limitation, N,N-dimethyl amoxapine, N-methyl trimipramine, N-methyl dothiepin, N-methyl doxepin, N-methyl amitriptyline, N,N-dimethyl protriptyline, N,N-dimethyl desipramine, N-methyl clomipramine, N-methyl clozapine, N-methyl loxapine, N,N-dimethyl nortriptyline, N-methyl cyclobenzaprine, N-methyl cyproheptadine, N-methyl olopatadine, N-methyl promethazine, N-methyl trimeprazine, N-methyl chlorprothixene, N-methyl chlorpromazine, N-methyl propiomazine, N-methyl moricizine, N-methyl prochlorperazine, N-methyl thiethylperazine, N-methyl fluphena
  • ion channel blockers that can contain an amine nitrogen which can be guanylated or quaternized as described herein include, without limitation, orphenadrine, phenbenzamine, bepridil, pimozide, penfluridol, flunarizine, fluspirilene, propiverine, disopyramide, methadone, tolterodine, tridihexethyl salts, tripelennamine, mepyramine, brompheniramine, chlorpheniramine, dexchlorpheniramine, carbinoxamine, levomethadyl acetate, gallopamil, verapamil, devapamil, tiapamil, emopamil, dyclonine, pramoxine, lamotrigine, fendiline, mibefradil, gabapentin, amiloride, diltiazem, nifedipine, nimodipine, nitrendipine
  • Still other ion channel blockers can be modified to incorporate a nitrogen atom suitable for quaternization or guanylation.
  • These ion channel blockers include, without limitation, fosphenyloin, ethotoin, phenyloin, carbamazepine, oxcarbazepine, topiramate, zonisamide, and salts of valproic acid.
  • channel blockers including still other derivatives that can be quaternized or guanylated according to the methods described herein are provided in Table 1.
  • 4,552,695 see, e.g., the compound of Formula (I)
  • 32 nifedipine U.S. Pat. No. 3,485,847 see, e.g., the Formula described at col. 1, line 40-col. 2, line 6, the compounds of Examples 1-6, and claims 1-27)
  • 33 nimodipine U.S. Pat. No. 3,799,934 see, e.g., the Formula described at col. 1, lines 39- 69, the compounds described at col. 4, line 50-col. 5, line 16, Examples 1-53, and claims 1-13
  • Exemplary cationic calcium channel blockers include D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium.
  • Other exemplary compounds include any charged derivative, e.g., a quarternary amine derivative, of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, terpene compounds (e.g., sesquiterpenes) such as those described in Norman et al.
  • Yamamoto et al. provides the following N-type calcium channel blockers (Table 2), which can be modified (e.g., quaternized or guanylated) according to the methods described herein.
  • each R 11A , R 11B , and R 11C is selected, independently, from H or C 1-4 alkyl, and where 0, 1, 2, or 3 of the dashed bonds represents a carbon-carbon double bond (i.e., compounds of Formula (XI) can include 0, 1, 2, or 3 double bonds), provided that when 2 or 3 carbon-carbon double bonds are present, the double bonds are not adjacent to one another.
  • compounds that include 0, 1, or 2 double bonds can be prepared according to methods known in the literature, e.g., partial or total hydrogenation of the parent triene.
  • compounds of Formula (XI) can be represented by the following formula (XI-A),
  • each R 11A , R 11B , R 11C , and X is according to Formula (XI), and where each dashed bond represents an optional carbon-carbon double bond.
  • Still other farnesyl amine compounds can include those compounds that have a structure according to Formula (XI-B),
  • R 11A , R 11B , R 11C , and X is according to Formula (XI).
  • Exemplary compounds of Formula (XI) include
  • Amino acid derivatives e.g., those described in U.S. Pat. No. 7,166,590 or in Seko et al., Bioorg. Med. Chem. Lett. 11(16):2067-2070 (2001), each of which is herein incorporated by reference, can also be used in the invention.
  • compounds having a structure according to Formula (XII) can be N-type calcium channel blockers.
  • each of R 12A , R 12B , R 12C , and R 12D is independently, selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-40 alkcycloalkyl, and C 3-10 alkheterocyclyl; or R 12A and R 12B together complete a heterocyclic ring having at least one nitrogen atom, n is an integer between 1-5, each of R 12E and R 12F is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, or C 3-10 alkheterocyclyl, and X is any pharmaceutically acceptable anion.
  • Exemplary compounds of Formula (XII) include
  • Still other compounds that can be used in the invention are charged derivatives of flunarizine and related compounds (see, e.g., U.S. Pat. Nos. 2,883,271 and 3,773,939, as well as Zamponi et al., Bioorg. Med. Chem. Lett. 19: 6467 (2009)), each of which is hereby incorporated by reference.
  • compounds according to Formulas (XIII-A), (XIII-B), and (XIII-C) can be prepared according to, e.g., Zamponi et al., and used in the invention,
  • each R 13A -R 13J and R 13O -R 13T is selected, independently, from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2A alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl, OR 13AA , NR 13AB R 13AC , NR 13AD C(O)R 13AE , S(O)R 13AF , SO 2 R 13AG R 13AH , SO 2 NR 13AI R 13AJ , SO 3 R 13AK , CO 2 R 13AL , C(O)R 13AM , and C(O)NR 13AN R 13AO ; and each of R 13AA -R 13AO is , independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl;
  • each R 13K , R 13L , R 13M , and R 13N is, independently, H or C 1-4 alkyl, or R 13K and R 13L , or R 13M and R 13N , combine to form C ⁇ O, or R 13K and R 13M combine to form C ⁇ C;
  • R 13Y is H or C 1-4 alkyl
  • R 13Z and R 13Z′ are, independently, selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl; and
  • X ⁇ is any pharmaceutically acceptable anion.
  • Exemplary compounds according to Formulas (XIII-A)-(XIII-C) include
  • mibrefradil such as those described in U.S. Pat. No. 4,808,605, hereby incorporated by reference can also be used.
  • exemplary mibrefadil derivatives include compounds of Formula (XIV),
  • n is an integer between 0-5;
  • R 14A is heterocyclyl (e.g., a heteroaryl such as benzimidazole),
  • each of R 14B , R 14C , R 14D , and R1 4E is, independently, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl; and
  • R 14F is selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, C 7-14 alkaryl, C 3-10 alkcycloalkyl, and C 3-10 alkheterocyclyl, OR 14G , NR 14H R 14I , NR 14J C(O)R 14K , S(O)R 14L , SO 2 R 14M R 14N , SO 2 NR 14O R 14P , SO 3 R 14Q , CO 2 R 14R , C(O)R 14S , and C(O)NR 14T R 14V ; and each of R 14G -R 13AO is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl.
  • Charged derivatives of 4-piperidinylaniline compounds can be prepared according to methods known in the literature and described herein.
  • charged N-alkyl derivatives e.g., N-methyl
  • Compounds (86)-(88) can be prepared and used in the compositions, methods, and kits described herein.
  • channel blockers that can be quaternized or guanylated according to the methods described herein are described, for example, in PCT Publication No. WO 2004/093813 (see, e.g., Tables 5, 6, and 8), which is herein incorporated by reference.
  • the channel blockers shown in Table 3 can be quaternized or guanylated as described herein.
  • charge-modified ion channel blockers may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of the parent ion channel blocker, the linker, the bulky group, and/or the charged group.
  • protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitrophenyl.
  • amides such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides.
  • protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho-esters, and halo-esters.
  • Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy-trityls), and silyl ethers.
  • Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls.
  • sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides).
  • Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule.
  • the conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis (2 nd Ed.), John Wiley & Sons, 1991 and P. J. Kocienski, Protecting Groups , Georg Thieme Verlag, 1994.
  • Charge-modified ion channel blockers can be prepared using techniques familiar to those skilled in the art. The modifications can be made, for example, by alkylation of the parent ion channel blocker using the techniques described by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure , John Wiley & Sons, Inc., 1992, page 617.
  • the conversion of amino groups to guanidine groups can be accomplished using standard synthetic protocols. For example, Mosher has described a general method for preparing mono-substituted guanidines by reaction of aminoiminomethanesulfonic acid with amines (Kim et al., Tetrahedron Lett. 29:3183 (1988)).
  • guanidine is part of a heterocyclic ring having two nitrogen atoms (see, for example, the structures below).
  • the ring system can include an alkylene or
  • alkenylene of from 2 to 4 carbon atoms e.g., ring systems of 5, 6, and 7-membered rings.
  • ring systems can be prepared, for example, using the methods disclosed by Schlama et al., J. Org. Chem. 62:4200 (1997).
  • Charge-modified ion channel blockers can be prepared by alkylation of an amine nitrogen in the parent compound as shown in Scheme 1.
  • charge-modified ion channel blockers can be prepared by introduction of a guanidine group.
  • the parent compound can be reacted with a cynamide, e.g., methylcyanamide, as shown in Scheme 2 or pyrazole-1-carboxamidine derivatives as shown in Scheme 3 where Z is H or a suitable protecting group.
  • the parent compound can be reacted with cyanogens bromide followed by reaction with methylchloroaluminum amide as shown in Scheme 4.
  • Reagents such as 2-(methylthio)-2-imidazoline can also be used to prepare suitably functionalized derivatives (Scheme 5).
  • Any ion channel blocker containing an amine nitrogen atom e.g., a compound selected from Compounds (1)-(563) or a compound according to Formulas (I)-(XIV)
  • a compound selected from Compounds (1)-(563) or a compound according to Formulas (I)-(XIV) can be modified as shown in Schemes 1-5.
  • TRPV1 agonists that can be employed in the methods and kits of the invention include but are not limited to any that activates TRPV1 receptors on nociceptors and allows for entry of at least one inhibitor of voltage-gated ion channels.
  • a suitable TRPV1 agonist is capsaicin or another capsaicinoids, which are members of the vanilloid family of molecules. Naturally occurring capsaicinoids are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, and nonivamide, whose structures are provided below.
  • capsaicinoids and capsaicinoid analogs and derivatives for use in the compositions and methods of the present invention include naturally occurring and synthetic capsaicin derivatives and analogs including, e.g., vanilloids (e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and other capsinoids, capsiconiate, dihydrocapsiconiate and other coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide, N-oleyl-homovanillamide
  • TRPV1 agonists include but are not limited to eugenol, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxycicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoe
  • TRPV1 agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.
  • TRP1A agonists that can be employed in the methods and kits of the invention include any that activates TRP1A receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels.
  • Suitable TRP1A agonists include but are not limited to cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597).
  • Still other agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.
  • P2X agonists that can be employed in the methods and kits of the invention include any that activates P2X receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels.
  • Suitable P2X agonists include but are not limited to 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate).
  • TRPM8 agonists that can be employed in the methods and kits of the invention include any that activates TRPM8 receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels.
  • Suitable TRPM8 agonists include but are not limited to menthol, iciclin, eucalyptol, linalool, geraniol, and hydroxycitronellal.
  • one or more additional biologically active agents typically used to treat neurogenic inflammation may be used in combination with a composition of the invention described herein.
  • the biologically active agents include, but are not limited to, acetaminophen, NSAIDs, glucocorticoids, narcotics (e.g. opioids), tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative agents, and immune modulators.
  • the biologically active agents can be administered prior to, concurrent with, or following administration of a composition of the invention, using any formulation, dosing, or administration known in the art that is therapeutically effective.
  • Non-steroidal anti-inflammatory drugs that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, acetylsalicylic acid, amoxiprin, benorylate, benorilate, choline magnesium salicylate, diflunisal, ethenzamide, fatelamine, methyl salicylate, magnesium salicylate, salicyl salicylate, salicylamide, diclofenac, aceclofenac, acemethacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, f
  • Narcotics that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited, to tramadol, hydrocodone, oxycodone, morphine, and pharmaceutically acceptable salts thereof.
  • Antiproliferative and immune modulatory agents that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF-alpha agonists, TNF-alpha antagonists or scavengers, interleukin 1 (IL-1) antagonists or scavengers, endothelin A receptor antagonists, retinoic acid receptor agonists, hormonal agents, antihormonal agents, photodynamic agents, and
  • the administration of a combination of the invention may be by any suitable means that results in the reduction of inflammation at the target region (e.g., any inflamed tissue or mucosal surface).
  • the inhibitor(s) of voltage-gated ion channels may be contained in any appropriate amount in any suitable carrier substance, and are generally present in amounts totaling 1-95% by weight of the total weight of the composition.
  • composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, gastrointestinal, reproductive or oral mucosa.
  • parenteral e.g., intravenous, intramuscular
  • rectal cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, gastrointestinal, reproductive or oral mucosa.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols.
  • the compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • Each compound of a combination therapy may be formulated in a variety of ways that are known in the art.
  • the first and second agents of the combination therapy may be formulated together or separately.
  • the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents.
  • kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc.
  • the kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
  • the unit dose kit can contain instructions for preparation and administration of the compositions.
  • the kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”).
  • the kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.
  • Each compound of the invention can be formulated for controlled release (e.g., sustained or measured) administration, as described in U.S. Patent Application Publication Nos. 2003/0152637 and 2005/0025765, each incorporated herein by reference.
  • a compound of the invention, alone or in combination with one or more of the biologically active agents as described herein can be incorporated into a capsule or tablet, that is administered to the site of inflammation.
  • Any pharmaceutically acceptable vehicle or formulation suitable for local infiltration or injection into a site to be treated e.g., a painful surgical incision, wound, or joint
  • a sustained release of compound of the invention alone or in combination with one or more of the biologically active agents as described herein, may be employed to provide for prolonged elimination or alleviation of inflammation, as needed.
  • Slow release formulations known in the art include specially coated pellets, polymer formulations or matrices for surgical insertion or as sustained release microparticles, e.g., microspheres or microcapsules, for implantation, insertion, infusion or injection, wherein the slow release of the active medicament is brought about through sustained or controlled diffusion out of the matrix and/or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix.
  • Other formulations or vehicles for sustained or immediate delivery of an agent to a preferred localized site in a patient include, e.g., suspensions, emulsions, gels, liposomes and any other suitable art known delivery vehicle or formulation acceptable for subcutaneous or intramuscular administration.
  • biocompatible materials may be utilized as a controlled release carrier to provide the controlled release of a compound of the invention, alone or in combination with one or more biologically active agents, as described herein.
  • Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art may be utilized. It is preferred that the biocompatible controlled release material degrade in vivo within about one year, preferably within about 3 months, more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50% of the material degrading into non-toxic residues, which are removed by the body, and 100% of the compound of the invention being released within a time period within about two weeks, preferably within about 2 days to about 7 days.
  • a degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that release is not only sustained but also provides desirable release rates.
  • the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local anesthetic effect over the desired time period.
  • Suitable biocompatible polymers can be utilized as the controlled release material.
  • the polymeric material may comprise biocompatible, biodegradable polymers, and in certain preferred embodiments is preferably a copolymer of lactic and glycolic acid.
  • Preferred controlled release materials which are useful in the formulations of the invention include the polyanhydrides, polyesters, co-polymers of lactic acid and glycolic acid (preferably wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 i.e., 80% or less lactic acid to 20% or more glycolic acid by weight)) and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride.
  • polyesters include polylactic acid, polyglycolic acid and polylactic acid-polyglycolic acid copolymers.
  • Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen and polysaccharides such as hyaluronic acid.
  • the polymeric material may be prepared by any method known to those skilled in the art.
  • this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539, incorporated herein by reference.
  • copolymers of lactic and glycolic acid may be prepared by any other procedure known to those skilled in the art.
  • polymers include polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters or mixtures or blends of any of these.
  • Pharmaceutically acceptable polyanhydrides which are useful in the present invention have a water-labile anhydride linkage. The rate of drug release can be controlled by the particular polyanhydride polymer utilized and its molecular weight.
  • the polysaccharides may be poly-1,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof.
  • the biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-1,4-glucan, including hydrolyzed amylopectin, hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like.
  • the polyanhydride polymer may be branched or linear.
  • polymers which are useful in the present invention include (in addition to homopolymers and copolymers of poly(lactic acid) and/or poly(glycolic acid)) poly[bis(p-carboxyphenoxy)propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated aliphatic acids, polyanhydride polymers prepared from amino acids which are modified to include an additional carboxylic acid, aromatic polyanhydride compositions, and co-polymers of polyanhydrides with other substances, such as fatty acid terminated polyanhydrides, e.g., polyanhydrides polymerized from monomers of dimers and/or trimers of unsaturated fatty acids or unsaturated aliphatic acids.
  • PCPP bis(p-carboxyphenoxy)propane anhydride]
  • PCPM poly[bis(p-carboxy)methane anhydride]
  • Polyanhydrides may be prepared in accordance with the methods set forth in U.S. Pat. No. 4,757,128, incorporated herein by reference.
  • Polyorthoester polymers may be prepared, e.g., as set forth in U.S. Pat. No. 4,070,347, incorporated herein by reference.
  • Polyphosphoesters may be prepared and used as set forth in U.S. Pat. Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581, each of which is incorporated herein by reference.
  • Proteinaceous polymers may also be used. Proteinaceous polymers and their soluble derivatives include gelation biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like.
  • Biodegradable synthetic polypeptides include poly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine, copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.
  • the controlled release material which in effect acts as a carrier for a compound of the invention, alone or in combination with one or more biologically active agents as described herein, can further include a bioadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins or the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan.
  • a bioadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins or the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan.
  • the biodegradable polymer comprises a gel
  • one such useful polymer is a thermally gelling polymer, e.g., polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer such as PluronicTM F127 from BASF Wyandotte.
  • the local anesthetic formulation may be injected via syringe as a free-flowing liquid, which gels rapidly above 30° C. (e.g., when injected into a patient).
  • the gel system then releases a steady dose of a compound of the invention, alone or in combination with one or more biologically active agents as described herein, at the site of administration.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose
  • Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned.
  • the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • the oral dosage of any of the compounds of the combination of the invention will depend on the nature of the compound, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be necessary.
  • Administration of each drug in a combination therapy can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases.
  • composition of the invention alone or in combination with one or more of the biologically active agents described herein, can also be adapted for topical use with a topical vehicle containing from between 0.0001% and 25% (w/w) or more of active ingredient(s).
  • the active ingredients are preferably each from between 0.0001% to 10% (w/w), more preferably from between 0.0005% to 4% (w/w) active agent.
  • the cream can be applied one to four times daily, or as needed.
  • the topical vehicle containing the composition of the invention, or a combination therapy containing a composition of the invention is preferably applied to the site of inflammation on the patient.
  • a cream may be applied to the hands of a patient suffering from arthritic fingers.
  • compositions of the invention can be formulated for nasal or intranasal administration.
  • Formulations suitable for nasal administration when the carrier is a solid, include a coarse powder having a particle size, for example, in the range of approximately 20 to 500 microns which is administered by rapid inhalation through the nasal passage.
  • the carrier is a liquid, for example, a nasal spray or as nasal drops, one or more of the formulations can be admixed in an aqueous or oily solution, and inhaled or sprayed into the nasal passage.
  • the active ingredient can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg/kg) on the edema elicited by injection of complete Freund's adjuvant (CFA) in the rat hindpaw determined by measuring the total volume of the hindpaw by plethysmography.
  • CFA complete Freund's adjuvant
  • the degree of swelling produced by injection of CFA is reduced by administration of QX-314 reflecting reduction in neurogenic edema resulting from the blockade of nociceptors by QX314.
  • QX-314 by itself has no effect different from administration of saline.
  • N-methyl-verapamil a charged derivative of the known calcium channel blocker verapamil and structurally related to D-890, can be loaded into dorsal root ganglion neurons through activation of TRPV1 channels by capsaicin.
  • the internally-loaded N-methyl-verapamil then produces long-lasting inhibition of the voltage-dependent calcium channels in the neurons. Entry of the drug into the cell, and its blocking action, depends on applying the drug in the presence of capsaicin to activate the TRPV1 channels present in the neuronal membrane.
  • FIG. 2 the inhibition of voltage-dependent calcium channel current in a DRG neuron by N-methyl-verapamil applied in the presence of capsaicin to open TRPV1 channels.
  • the traces show currents through voltage-activated calcium channels in a dissociated rat dorsal root ganglion neuron, recorded in whole-cell mode. Current was carried by 2 mM Ba 2+ on a background of 155 mM N-methyl-D-glucamine (to eliminate Na current), with an internal CsCl-based solution. Calcium channels were opened by a voltage step from ⁇ 80 mV to ⁇ 20 mV. When channels are opened, inward-going current is carried by Ba 2+ ions flowing into the cell.
  • Each panel shows calcium channel currents before and 3 minutes after exposure of the cell to either 1 ⁇ M capsaicin alone (top panel), 300 ⁇ M N-methyl-verapamil alone (middle panel), or 300 ⁇ M N-methyl-verapamil applied in the presence of 1 ⁇ M capsaicin to open TRPV1 channels (bottom panel).
  • Control experiments using either capsaicin alone or N-methyl-verapamil alone each produce weak, transient effects that are rapidly reversed when the agents are washed away.
  • the combination produces an inhibition of calcium channel currents that persists after washout of the agents, consistent with N-methyl-verapamil having entered through TRPV1 channels and remaining trapped inside the cells, blocking the calcium channels from the inside.

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10159268B2 (en) 2013-02-08 2018-12-25 General Mills, Inc. Reduced sodium food products
US10420756B2 (en) 2015-03-26 2019-09-24 Sen-Jam Pharmaceutical Llc. Methods and compositions to inhibit symptoms associated with veisalgia
US10729664B2 (en) 2009-07-10 2020-08-04 President And Fellows Of Harvard College Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10799502B2 (en) * 2013-05-24 2020-10-13 Societe Des Produits Nestle S.A. Treatment or prevention of non-inflammatory neuronal damage from brain trauma and strokes using Menthol, Linalool and/or Icilin
US10842798B1 (en) 2019-11-06 2020-11-24 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2021022056A1 (en) 2019-07-31 2021-02-04 Foamix Pharmaceuticals Ltd. Compositions and methods and uses thereof
US10927096B2 (en) 2019-03-11 2021-02-23 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US10934263B2 (en) 2019-03-11 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10968179B2 (en) 2019-03-11 2021-04-06 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11021443B2 (en) 2015-08-03 2021-06-01 President And Fellows Of Harvard College Charged ion channel blockers and methods for use
US11332446B2 (en) 2020-03-11 2022-05-17 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2023235391A1 (en) * 2022-05-31 2023-12-07 Sorrento Therapeutics, Inc. Method for treating inflammatory dysfunction of the oral mucosa
US12138274B2 (en) 2018-11-08 2024-11-12 Board Of Regents Of The University Of Nebraska Compositions and methods for the treatment of peripheral artery disease and cardiopulmonary diseases
US12162851B2 (en) 2020-03-11 2024-12-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010510227A (ja) 2006-11-20 2010-04-02 プレジデント アンド フェロウズ オブ ハーバード カレッジ 痛みおよび痒みの治療方法、組成物およびキット
US20130203715A1 (en) * 2010-07-20 2013-08-08 Pulmatrix, Inc. Use of trp channel agonists to treat infections
US20130164338A1 (en) 2010-08-30 2013-06-27 Pulmatrix, Inc. Treatment of cystic fibrosis using calcium lactate, leucine and sodium chloride in a respiraple dry powder
CA3086367A1 (en) 2010-09-29 2012-04-05 Pulmatrix Operating Company, Inc. Monovalent metal cation dry powders for inhalation
US20140031341A1 (en) * 2010-12-22 2014-01-30 Universitat Munster Modulators and methods for the treatment of rosacea
CA2822723A1 (en) * 2010-12-22 2012-06-28 Galderma Research & Development Modulators of trpa1 for the treatment of rosacea
US8865741B2 (en) 2011-02-18 2014-10-21 Asana Biosciences, Llc Aminoindane compounds and use thereof in treating pain
EP2771320B1 (en) 2011-10-24 2016-06-22 Endo Pharmaceuticals Inc. Cyclohexylamines
WO2013141202A1 (ja) * 2012-03-21 2013-09-26 独立行政法人国立精神・神経医療研究センター 筋増加剤、及び筋増加物質のスクリーニング方法
WO2014028675A1 (en) 2012-08-15 2014-02-20 Endo Pharmaceuticals Inc. Use of aminoindane compounds in treating overactive bladder and interstitial cystitis
AU2014248455B2 (en) 2013-04-01 2018-12-06 Pulmatrix Operating Company, Inc. Tiotropium dry powders
US20160096815A1 (en) 2013-05-23 2016-04-07 Kinki University T-type calcium channel inhibitor
JP2016524609A (ja) * 2013-05-24 2016-08-18 ネステク ソシエテ アノニム メントール及び／又はイシリンを用いるうつ病の処置又は予防
WO2015051336A1 (en) 2013-10-03 2015-04-09 David Wise Compositions and methods for treating pelvic pain and other conditions
CN106214670B (zh) * 2016-07-25 2020-12-29 上海璃道医药科技有限公司 酰胺类药物的用途
CN106220562B (zh) * 2016-07-29 2019-10-01 上海璃道医药科技有限公司 两种喹啉环类药物的新用途
CN106892875B (zh) * 2016-11-11 2018-03-02 杭州唯铂莱生物科技有限公司 钙离子通道阻滞剂化合物及其制备方法和应用
WO2019173394A1 (en) 2018-03-05 2019-09-12 Wylder Nation Foundation Compositions and methods for activating signaling through the cb1 cannabinoid receptor for treating and preventing diseases and disorders characterized by abnormal cellular accumulation of sphingolipids such as sphingomyelin
WO2019183470A2 (en) 2018-03-22 2019-09-26 Incarda Therapeutics, Inc. A novel method to slow ventricular rate
CN108467337B (zh) * 2018-04-23 2020-12-15 中国科学院烟台海岸带研究所 一种倍半萜烯醇类化合物及其制备和应用
CN108324685A (zh) * 2018-04-28 2018-07-27 武汉田田药业有限公司 一种盐酸氟桂利嗪口服溶液的生产工艺
US11020384B2 (en) 2019-08-01 2021-06-01 Incarda Therapeutics, Inc. Antiarrhythmic formulation
WO2023064489A1 (en) * 2021-10-14 2023-04-20 Galileo Biosystems, Inc. Aryl hydrocarbon receptor (ahr) modulators and therapeutic uses thereof
CN114853630B (zh) * 2022-06-07 2023-06-27 温州医科大学 一种2,6-二苯亚甲基环己酮肟类化合物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6355637B1 (en) * 1999-10-01 2002-03-12 Advanced Medicine, Inc. Local anesthetic compounds
US20060062739A1 (en) * 2004-09-20 2006-03-23 Thomas Hofmann Inhalable lidocaine formulation for treatment of asthma and for reducing the need for corticosteroids in asthmatic patients
US20080312212A1 (en) * 2005-12-22 2008-12-18 Novartis Ag Organic Compounds
US20090054485A1 (en) * 2000-06-23 2009-02-26 Gleich Gerald J Method of treating neutrophil-related diseases with topical anesthetics

Family Cites Families (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE151036C (enExample)
DE150423C (enExample)
US812554A (en) 1905-11-08 1906-02-13 Hoechst Ag Alkamin esters of para-aminobenzoic acid.
US1889645A (en) 1930-12-22 1932-11-29 Winthrop Chem Co Inc Beta-dimethylaminoethyl ester of para-butylamino-benzoic acid
US2441498A (en) 1943-07-15 1948-05-11 Astra Apotekarnes Kem Fab Alkyl glycinanilides
US2689248A (en) 1950-06-17 1954-09-14 Sterling Drug Inc Tertiary-aminoalkyl 4-amino-2-alkoxybenzoates and their synth esis
US2799679A (en) 1955-04-28 1957-07-16 Bofors Ab Process of preparing amides of heterocyclic carboxylic acids
US2883271A (en) 1956-11-23 1959-04-21 Phillips Petroleum Co Safety system for combustion process
US2955111A (en) 1957-01-28 1960-10-04 Bofors Ab Synthesis of n-alkyl-piperidine and n-alkyl-pyrrolidine-alpha-carboxylic acid amides
US3160662A (en) 1957-06-26 1964-12-08 Astra Apotekarnes Kem Fab Lower alkylaminoacyl amide anesthetics
NL281394A (enExample) 1961-07-25
DE1251764B (de) 1965-08-18 1967-10-12 C H Boehnnger Sohn Ingelheim/ Rhein Verfahren zur Herstellung von antimikrobiell wirksamen 12 3,4-Tetra hydro 9 -ammo acridmiumverbmdungen
US3812147A (en) 1970-12-22 1974-05-21 Astra Pharma Prod Acylxylidide local anaesthetics
US3931195A (en) 1971-03-03 1976-01-06 Mead Johnson & Company Substituted piperidines
BE786875A (fr) 1971-07-28 1973-01-29 Astra Pharma Prod Amide, methode pour sa preparation et ses compositions therapeutiques
US3773939A (en) 1971-11-24 1973-11-20 Janssen Pharmaceutica Nv N-arallyl-n'-aralkyl piperazine pharmaceutical compositions
US4069309A (en) 1972-09-19 1978-01-17 Avon Products, Inc. Cationic skin substantive sunscreen composition and method
US3900481A (en) 1974-04-01 1975-08-19 Riker Laboratories Inc Derivatives of pyrrolidine and piperidine
CS195321B2 (en) 1975-12-23 1980-01-31 Ciba Geigy Ag Plant growth suppressing agents
US4070347A (en) 1976-08-16 1978-01-24 Alza Corporation Poly(orthoester) co- and homopolymers and poly(orthocarbonate) co- and homopolymers having carbonyloxy functionality
DE2915250A1 (de) 1979-04-14 1980-10-30 Basf Ag Salze von alpha -aminoacetaniliden
US4293539A (en) 1979-09-12 1981-10-06 Eli Lilly And Company Controlled release formulations and method of treatment
US4877805A (en) 1985-07-26 1989-10-31 Kligman Albert M Methods for treatment of sundamaged human skin with retinoids
US4757128A (en) 1986-08-01 1988-07-12 Massachusetts Institute Of Technology High molecular weight polyanhydride and preparation thereof
US5169637A (en) 1983-03-24 1992-12-08 The Liposome Company, Inc. Stable plurilamellar vesicles
AU560367B2 (en) 1983-08-01 1987-04-02 Astra Lakemedel Aktiebolag L-n-n-propylpipecolic acid-2,6-xylidide and method for preparing the same
CA1237671A (en) 1983-08-01 1988-06-07 Michael W. Fountain Enhancement of pharmaceutical activity
US5409704A (en) 1985-06-26 1995-04-25 The Liposome Company, Inc. Liposomes comprising aminoglycoside phosphates and methods of production and use
US4975282A (en) 1985-06-26 1990-12-04 The Liposome Company, Inc. Multilamellar liposomes having improved trapping efficiencies
US5023087A (en) 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system
IE60901B1 (en) 1986-08-21 1994-08-24 Vestar Inc Improved treatment of systemic fungal infections with phospholipid particles encapsulating polyene antifungal antibiotics
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
CA1319144C (en) 1986-11-14 1993-06-15 Quirico Branca Tetrahydronaphthalene derivatives
US5032582A (en) 1987-02-27 1991-07-16 Liposome Technology, Inc. Method for treating fungal infections with amphotericin B/cholesterol sulfate composition
US4994213A (en) 1988-05-17 1991-02-19 Liposome Technology, Inc. Method of preparing lipid structures
US5082866A (en) 1988-06-01 1992-01-21 Odontex, Inc. Biodegradable absorption enhancers
US4980378A (en) 1988-06-01 1990-12-25 Odontex, Inc. Biodegradable absorption enhancers
US5194581A (en) 1989-03-09 1993-03-16 Leong Kam W Biodegradable poly(phosphoesters)
US5194266A (en) 1989-08-08 1993-03-16 Liposome Technology, Inc. Amphotericin B/cholesterol sulfate composition and method
US5356633A (en) 1989-10-20 1994-10-18 Liposome Technology, Inc. Method of treatment of inflamed tissues
DE69211691T2 (de) 1991-04-19 1997-01-16 Nexstar Pharmaceuticals Inc., Boulder, Col. Pharmazeutische formulierung und pharmazeutisches verfahren
US5176907A (en) 1991-08-13 1993-01-05 The Johns Hopkins University School Of Medicine Biocompatible and biodegradable poly (phosphoester-urethanes)
GR1002207B (en) 1992-08-06 1996-03-27 Johnson & Johnson Consumer Skin care compositions containing imidazoles.
US5552155A (en) 1992-12-04 1996-09-03 The Liposome Company, Inc. Fusogenic lipsomes and methods for making and using same
US5480971A (en) * 1993-06-17 1996-01-02 Houghten Pharmaceuticals, Inc. Peralkylated oligopeptide mixtures
US6051576A (en) 1994-01-28 2000-04-18 University Of Kentucky Research Foundation Means to achieve sustained release of synergistic drugs by conjugation
US5591317A (en) 1994-02-16 1997-01-07 Pitts, Jr.; M. Michael Electrostatic device for water treatment
US5716622A (en) 1995-01-06 1998-02-10 The Rockefeller University Functionally active regions of signal transducer and activators of transcription
US5783683A (en) 1995-01-10 1998-07-21 Genta Inc. Antisense oligonucleotides which reduce expression of the FGFRI gene
AU5938996A (en) 1995-06-07 1996-12-30 Nexstar Pharmaceuticals, Inc. Method for encapsulating pharmaceutical materials
US5747470A (en) 1995-06-07 1998-05-05 Gen-Probe Incorporated Method for inhibiting cellular proliferation using antisense oligonucleotides to gp130 mRNA
US6413961B1 (en) 1995-12-12 2002-07-02 Omeros Medical Systems, Inc. Irrigation solution and method for inhibition of pain and inflammation
SE508357C2 (sv) 1996-01-02 1998-09-28 Kay Laserow Mätinstrument för mätning av smärta jämte ett förfarande för att med ett mätinstrument mäta smärta
WO1998024428A1 (en) 1996-12-02 1998-06-11 Brigham & Women's Hospital, Inc. Long-acting local anesthetics
SE9604751D0 (sv) 1996-12-20 1996-12-20 Astra Ab New therapy
US5837713A (en) * 1997-02-26 1998-11-17 Mayo Foundation For Medical Education And Research Treatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids
EP0991699B1 (en) 1997-06-18 2002-04-24 Guilford Pharmaceuticals Inc. Two-stage solution polymerization of high molecular weight poly(phosphoesters)
US6028163A (en) 1997-06-27 2000-02-22 Guilford Pharmaceuticals Inc. Solution polymerization of high molecular weight poly(phosphoesters) in toluene
EP0997147B1 (en) 1997-07-08 2006-03-15 Ono Pharmaceutical Co., Ltd. Amino acid derivatives
TW536401B (en) 1997-09-03 2003-06-11 Cardiome Pharma Corp A pharmaceutical composition of N,N-bis(phenylcarbamoylmethyl)dimethylammomum chloride and derivatives for the treatment of pain
US6623040B1 (en) 1997-09-03 2003-09-23 Recot, Inc. Method for determining forced choice consumer preferences by hedonic testing
US6083996A (en) 1997-11-05 2000-07-04 Nexmed Holdings, Inc. Topical compositions for NSAI drug delivery
KR20010072593A (ko) 1998-06-09 2001-07-31 추후보정 기침 치료용 조성물 및 기침 치료방법
US6153212A (en) 1998-10-02 2000-11-28 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same
US6103255A (en) 1999-04-16 2000-08-15 Rutgers, The State University Porous polymer scaffolds for tissue engineering
US6118020A (en) 1999-05-19 2000-09-12 Nexmed Holdings, Inc. Crystalline salts of dodecyl 2-(N,N-dimethylamino)-propionate
AU2334501A (en) * 1999-12-15 2001-06-25 Ucb Farchim Sa Cyclic quaternary ammonium compounds
WO2001044218A1 (en) 1999-12-15 2001-06-21 Ucb Farchim S.A. Quaternary salts of n-substituted cyclic or acyclic amines as pharmaceuticals
WO2001045678A2 (de) 1999-12-21 2001-06-28 Id Pharma Gmbh Arzneimittel, verfahren zu dessen herstellung und dessen verwendung
WO2001083828A1 (en) 2000-05-04 2001-11-08 Dzgenes, Llc TGFβ-RII PROMOTER POLYMORPHISMS
DE10039449A1 (de) 2000-08-11 2003-07-24 Id Pharma Gmbh I Ins Verwendung einer lokalanästhetikumhaltigen Zusammensetzung zur Behandlung von Hyperalgesien
US6766319B1 (en) 2000-10-31 2004-07-20 Robert J. Might Method and apparatus for gathering and evaluating information
US6884782B2 (en) 2000-11-08 2005-04-26 Amgen Inc. STAT modulators
US20030152637A1 (en) 2001-01-25 2003-08-14 Mark Chasin Local anesthetic, and method of use
US20040146590A1 (en) 2001-03-22 2004-07-29 Iadarola Michael J Molecular neurochirurgie for pain control administering locally capsaicin or resinferatoxin
US20030027833A1 (en) 2001-05-07 2003-02-06 Cleary Gary W. Compositions and delivery systems for administration of a local anesthetic agent
EP1399440B1 (en) 2001-06-15 2009-06-03 Vertex Pharmaceuticals Incorporated 5-(2-aminopyrimidin-4-yl)benzisoxazoles as protein kinase inhibitors
ITMI20012025A1 (it) 2001-09-28 2003-03-28 Dompe Spa Sali di ammonio quaternari di omega-amminoalchilammidi di acidi r 2-aril-propionici e composizioni farmaceutiche che li contengono
AU2003254426A1 (en) 2002-08-02 2004-02-23 Universite Libre De Bruxelles Apolipoprotein l-i for the treatment or diagnosis of prypanosomaldiseases
EA012599B1 (ru) 2003-04-10 2009-10-30 Ньюроджескс, Инк. Способы и композиции для введения агонистов trpv1
US20040220187A1 (en) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders
WO2004093813A2 (en) 2003-04-22 2004-11-04 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of pain, inflammation or inflammation mediated disorders
ES2223277B1 (es) 2003-06-19 2006-03-01 Fernando Bouffard Fita Composicion anestesica para administracion topica.
US8361467B2 (en) 2003-07-30 2013-01-29 Depuy Spine, Inc. Trans-capsular administration of high specificity cytokine inhibitors into orthopedic joints
NO20034069L (no) 2003-09-12 2005-03-14 Aximed As Fremstilling og bruk av capsaicinderivater
US20070149469A1 (en) 2003-10-02 2007-06-28 Christian Korherr Medical use of tbk-1 or of inhibitors thereof
US20050142596A1 (en) 2003-11-14 2005-06-30 Krolewski Andrzej S. Methods of diagnosing renal and cardiovascular disease
PT1701941E (pt) 2003-12-11 2012-08-03 Univ Texas Compostos para o tratamento de doenças proliferativas celulares
US20070196866A1 (en) 2004-03-13 2007-08-23 Irm Llc Modulators of ion channel trpa1
US7161034B2 (en) 2004-04-20 2007-01-09 Dade Behring Inc. Lidocaine analogs and methods of making and using same
WO2005105814A1 (en) 2004-04-28 2005-11-10 Incyte Corporation Tetracyclic inhibitors of janus kinases
ES2542847T3 (es) 2004-06-02 2015-08-12 Neurogesx Inc. Formulaciones que comprenden capsaicina, un anestésico local y/o un agente antipruriginoso para el tratamiento del dolor
ES2651021T3 (es) 2004-07-24 2018-01-23 Laboratorios Del Dr. Esteve, S.A. Uso de compuestos activos sobre el receptor sigma para el tratamiento de alodinia mecánica
ITMI20041566A1 (it) 2004-07-30 2004-10-30 Indena Spa "trpv1 agonisti, formulazioni che li contengono e loro usi"
US7947682B2 (en) 2004-12-29 2011-05-24 University Of Southern California Substituted N′-pyrrolo[1,2-a]quinoxalin-4-yl-hydrazides as anti-cancer agents
US20060134008A1 (en) 2004-12-16 2006-06-22 Daniel Deaver Compositions and methods for pulmonary conditions
AR054416A1 (es) 2004-12-22 2007-06-27 Incyte Corp Pirrolo [2,3-b]piridin-4-il-aminas y pirrolo [2,3-b]pirimidin-4-il-aminas como inhibidores de las quinasas janus. composiciones farmaceuticas.
US20070149506A1 (en) 2005-09-22 2007-06-28 Arvanitis Argyrios G Azepine inhibitors of Janus kinases
ES2542989T3 (es) 2005-10-12 2015-08-13 Idera Pharmaceuticals, Inc. Compuestos oligonucleótidos inmuno reguladores (IRO) para modular la respuesta inmune basada en receptor semejante a Toll
KR101391900B1 (ko) 2005-12-13 2014-05-02 인사이트 코포레이션 야누스 키나아제 억제제로서의 헤테로아릴 치환된 피롤로［2,3-ｂ］피리딘 및 피롤로［2,3-ｂ］피리미딘
AU2006329202A1 (en) 2005-12-21 2007-06-28 Painceptor Pharma Corporation Compositions and methods for modulating gated ion channels
EP1867338A1 (en) 2006-05-30 2007-12-19 Université Libre De Bruxelles Pharmaceutical composition comprising apolipoproteins for the treatment of human diseases
JP2010510227A (ja) * 2006-11-20 2010-04-02 プレジデント アンド フェロウズ オブ ハーバード カレッジ 痛みおよび痒みの治療方法、組成物およびキット
EP2121692B1 (en) 2006-12-22 2013-04-10 Incyte Corporation Substituted heterocycles as janus kinase inhibitors
WO2009026107A1 (en) 2007-08-17 2009-02-26 Portola Pharmaceuticals, Inc. Protein kinase inhibitors
CN101156851A (zh) * 2007-09-27 2008-04-09 刘全胜 盐酸尼卡地平分散片及其制备方法
CA2717042A1 (en) 2008-03-11 2009-09-17 The General Hospital Corporation Methods, compositions, and kits for treating pain and pruritis
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8258144B2 (en) 2008-04-22 2012-09-04 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
NZ590372A (en) 2008-07-08 2012-09-28 Univ Texas Novel inhibitors of proliferation and activation of signal transducer and activator of transcription (stats)
DE102008037682A1 (de) * 2008-08-14 2010-04-08 Strackharn, Klaus, Dr.med. Verwendung äquipotenter Dosierungen von Lokalanästetika oder Derivaten davon zur Therapie chronischer Schmerzen
CN101347427A (zh) * 2008-09-22 2009-01-21 北京理工大学 一种沙坦化合物或其可药用盐和钙通道阻断剂或可药用盐的复方
CL2009001884A1 (es) 2008-10-02 2010-05-14 Incyte Holdings Corp Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco.
KR20110071108A (ko) 2008-10-06 2011-06-28 이데라 파마슈티칼즈, 인코포레이티드 고콜레스테롤혈증 및 고지혈증 및 이에 관련된 질병의 예방 및 치료에서 톨-유사 수용체의 저해제의 용도
WO2010111471A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
JP6205133B2 (ja) 2009-07-10 2017-09-27 プレジデント アンド フェローズ オブ ハーバード カレッジ 抗炎症剤としての恒久的に荷電したナトリウムおよびカルシウムチャンネルブロッカー
US9023355B2 (en) 2010-04-13 2015-05-05 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for treating renal disease
US9828637B2 (en) 2010-04-18 2017-11-28 Wake Forest University Health Sciences Methods of predicting predisposition to or risk of kidney disease
WO2012030912A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation 7-cyclylquinazoline derivatives and methods of use thereof
US8822537B2 (en) 2012-09-27 2014-09-02 Achelios Therapeutics, Inc. Topical ketoprofen composition
RU2018107695A (ru) 2015-08-03 2019-09-05 Президент Энд Феллоуз Оф Гарвард Колледж Заряженные блокаторы ионных каналов и способы их применения

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6355637B1 (en) * 1999-10-01 2002-03-12 Advanced Medicine, Inc. Local anesthetic compounds
US20090054485A1 (en) * 2000-06-23 2009-02-26 Gleich Gerald J Method of treating neutrophil-related diseases with topical anesthetics
US20060062739A1 (en) * 2004-09-20 2006-03-23 Thomas Hofmann Inhalable lidocaine formulation for treatment of asthma and for reducing the need for corticosteroids in asthmatic patients
US20080312212A1 (en) * 2005-12-22 2008-12-18 Novartis Ag Organic Compounds

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Allen et al. , Clinical Relevance of the neurotrophins and their receptors, Clinical Science, 2006, Vol. 110, pages 175-191. *
Caceres, A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma, 2009, PNAS, Vol. 106, No. 22, pages 9909-9104. *
Dux et al., Inhibition of the neurogenic inflammatory response by lidocaine in rat skin, 1996, Inflamm Res, Vol. 45, pages 10-13. *
Jia et al. , TRPV1 Receptor: A target for the treatment of Pain, Cough, Airway Disease and Urinary Incontinence, 2005, Drugs News and Perspectives, 18(3), 165, ABSTRACT ONLY. *
Lee et al., Role of TRPV1 in inflammation-induced airway hypersensitivity, 2009, Current Opinion in Pharmacology, Vol. 9, pages 243-249. *
Ni et al. Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors, 2006, Am. J. Physiol. Regul. Integr Comp. Physiol, 291: 541-550. *
Szallasi, "The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept, 2007, Nature reviews, Vol. 6, pages 357-373. *

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* Cited by examiner, † Cited by third party
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WO2021022056A1 (en) 2019-07-31 2021-02-04 Foamix Pharmaceuticals Ltd. Compositions and methods and uses thereof
US10842798B1 (en) 2019-11-06 2020-11-24 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11696912B2 (en) 2019-11-06 2023-07-11 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
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US11332446B2 (en) 2020-03-11 2022-05-17 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US12162851B2 (en) 2020-03-11 2024-12-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2023235391A1 (en) * 2022-05-31 2023-12-07 Sorrento Therapeutics, Inc. Method for treating inflammatory dysfunction of the oral mucosa

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