GB2447791A - Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome - Google Patents

Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome Download PDF

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GB2447791A
GB2447791A GB0805357A GB0805357A GB2447791A GB 2447791 A GB2447791 A GB 2447791A GB 0805357 A GB0805357 A GB 0805357A GB 0805357 A GB0805357 A GB 0805357A GB 2447791 A GB2447791 A GB 2447791A
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alkyl
hydrogen
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syndrome
alkyloxycarbonyl
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Philip Cohen
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University of Dundee
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

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Abstract

Pharmaceutical formulation of compound (I) may be useful in alleviating or minimising a symptom or condition observed in a Down's syndrome subject. Compound (I) may be harmine, harmaline, harmane or harmalol. The compounds may act on protein kinase DYRK / DYRK1a and may be useful to treat learning deficiencies associated with Down's syndrome. <EMI ID=1.1 HE=52 WI=70 LX=369 LY=1290 TI=CF>

Description

1 2447791 METHOD OF TREATING LEARNING IMPAIRMENT IN DOWN'S
SYNDROME SUBJECTS
Field of the Invention
The present invention provides compounds for use and methods of alleviating learning and/or mental impairment in people suffering from Down's syndrome.
Background to the Invention
People with Down's syndrome have an extra chromosome (number 21) in some or all of their cells. This results in physical and mental characteristics which often includes learning difficulties, common facial features and heart problems.
Approximately I in 1000 children born in the UK are affected by Down's syndrome.
Children with Down's syndrome usually learn to walk, talk, read and write, but more slowly than other children of their age and ultimate IQ is generally below average.
Screening tests are available that can assist parents to assess the risk of their unborn child having Down's syndrome and some parents may decide to terminate the pregnancy if their baby has Down's syndrome.
Babies with Down's syndrome are usually diagnosed in the first few days after birth. However, there are currently no drug therapies for alleviating symptoms, such as the mental and learning impairment associated with Down's syndrome.
An object of the present invention is to obviate and/or mitigate mental and/or learning impairment in people with Down's syndrome.
A further object of the invention is to provide compounds suitable for use in children with Down's syndrome to help treat the mental and/or learning impairment associated with Down's syndrome.
The present invention is based in part on work carried out by the present inventors in relation to the protein kinase DYRKIa (Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, Unterman TG, Cohen P. Biochem. J. 2001, 355, 597-607 The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site; Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG. Biochem. J. 2001, 355, 609-615 The kinase DYRJ( 1 A phosphorylates protein-synthesis initiation factor eIF2Bc at Ser 539 and the microtubule-associated protein tau at Thr 212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase). Since those with Down's tend to have a problem converting phenylalanine into tyrosine, it is possible that DYRJ( (dual-specificity tyrosine -regulated kinase) may have some involvement in regulating this reaction. Moreover, DYRK1a is known to map to the "Down's syndrome critical region"(Gujmera J, Casas C, Pucharos C, Solans A, Domenech A, Planas AM, Ashley J, Lovett M, Estivill X, Pritchard M. Hum Mol Genet.
1996, 5, 1305-13 10. A human homologue of Drosophila minibrain (MNB) is expressed in neuronal regions affected in Down syndrome and maps to the critical region) and animals over-expressing DYR.Kla have learning and memory deficiencies. (Smith Di, Stevens ME, Sudanagunta SP, Bronson RT, Makhirison M, Watabe AM, O'Dell Ti, Fung J, Weier HU, Cheng iF, Rubin EM. Nat Genet.
1997,16(1):8-9. Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome) and may therefore be seen as a possible target for treating learning deficiencies associated with Downs.
In a first aspect there is provided use of a compound or salt or hydroxide thereof of the following formula (I) R3/ wherein R1 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino; halo or oxo; R2 and R3 are independently selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino or halo; and R4 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxycarbonyl; the dashed line represents a single or double bond, for the manufacture of a medicament for alleviating or minimising a symptom or condition observed in a Down's syndrome subject.
Typically the compound is used to improve and/or alleviate deficiencies in learning as experienced by subjects with Down's syndrome. Generally, Down's syndrome subjects are born with a brain capacity (IQ) similar to subjects without Down's syndrome, but as they grow, Down's syndrome subjects generally display a slower andlor reduced learning capacity such that by age 13, Down's syndrome subjects display a mean IQ below 50. It is envisaged therefore that the compounds of the present invention may be administered to a Down's syndrome subject from birth, or soon thereafter, until adolescence or possibly into and during adulthood.
In a further aspect there is provided a method of treating or preventing a learning impairment or deficiency in a subject suffering from Down's syndrome, the method comprising administering to the Down's syndrome subject a compound or salt or hydroxide thereof of the following formula (I) R3/ wherein R1, R2, R3 and R4 and the dashed line have the same meanings as given herein above.
The above method may generally be practised on Down's syndrome subjects from birth to adolescence.
Preferably R1, R2 and R3 are independently selected from hydrogen, hydroxyl or C1-C6 alkyl or alkyloxy; and R4 is selected from hydrogen or C1-C6 alkyl.
Typical salts may be formed by preparing a quaternary ammonium salt at one or more of the nitrogen atoms. For example, reaction with an inorganic or organic acid may be used to protonate the nitrogen atom to provide a positively charged nitrogen which is charge balanced with an anion species. Similarly, a hydroxide derivative may be provided by reaction with water.
Particularly preferred compounds are: Harmine, where R1 is H, R2 is CH3, R3 is OCH3, R1 is H and the dashed line is a double bond; Harmaljne, where R1 is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a single bond; Harmane, where R1 is H, R2 is CH3, R3 is H, R4 is H and the dashed line is a double bond; and Harmalol, where R1 is H, R2 is CH3, R3 is OH, R4 is H and the dashed line is a single bond.
Harmine is an alkaloid from seeds of Peganum harmala L., Zygophyllaceae. It is an active ingredient of hallucinogenic drinks made in the western Amazon region from related plants. There is no known therapeutic use but it was suggested to be a cure for postencephalitic Parkinson disease in the 1920's.
For use according to the present invention, the compounds or physiologically acceptable salt, hydroxide or other physiologically functional derivative thereof described herein may be presented as a pharmaceutical formulation, comprising the compound or physiologically acceptable salt, hydroxide or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic andlor prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intraderrnal, intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent.
Tablets may be optionally coated and, if uncoated, may optionally be scored.
Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. An active compound may also be formulated as dispersable granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.
Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release -controlling matrix, or is coated with a suitable release -controlling film.
Such formulations may be particularly convenient for prophylactic use.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials comnionly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
Injectible preparations may be adapted for bolus injection or Continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
Formulations suitable for pulmonary administration the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.
As one possibility such formulations are in the form of finely comminuted powders which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactarit and/or a solid diluent. Suitable liquid propellants include propane and the chiorofluorocarbons, and suitable gaseous propellarits include carbon dioxide.
Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.
Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
As a further possibility an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w/v of an active compound in aqueous or oily solution or suspension.
It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations described above may include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents aie propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
Dosages of the compounds of the present invention include those sufficient to provide the benefical effects for alleviating or minimising a symptom or condition observed in a Down's syndrome subject, whilst not eliciting an hallucinogenic effect on the subject.
Detailed description
Materials and Methods Kinase assays All assays (25.5111) were carried out at room temperature (21 C) and were linear with respect to time and enzyme concentrations under the conditions used.
Assays were performed for 30 minutes except assays for LCK and PKB which were performed for 15 minutes using Multidrop Micro reagent dispensers (Thermo Electron Corporation, Waltham, MA 02454, USA) in a 96-well format.
The concentration of magnesium acetate and [T-33P] ATP (800cpmlpmol) in the assays was one of three concentrations (5, 20 or 50.tM) in order to be at or below Km for ATP for the enzyme. Assays were initiated with MgATP and stopped by addition of of 0.5M orthophosphoric acid. Assays were then harvested Onto P81 filterplates using a unifilter harvester (PerkinElmer, Boston, MA 02118, USA), with a wash buffer of 50 mM orthophosphoric acid. Filterplates were then air dried overnight. I 0tl of Microscint 0 was added per well prior to counting for radioactivity.
MKKI, INKJSAPKIc, SAPK2a/p38, SAPK2b/p38j32, SAPK3/p38y, SAPK4/p38ö, MAPK2/ERJ(2, MAPKAP-K1j3, MAPKAP-K2, MSKI, PRAK, PKA, PKCa, PDKI, SGK, p7OS6K, GSK3I3, ROCK-Il, PRK2, AMPK, CHKI, CHK2, CK2, PHK, LCK, were assayed according to Davies et a!., (Davies, S.P., Reddy, H., Caivano, M. and Cohen, P. Biochem. J. 351, 95-105, 2000.
CSK and CDK2/cycljnA, were assayed according to Bain et al. (Bain J, McLauchlari 1-i, Elliott M, Cohen P. Biochem J. 371, 199-204, 2003., except that ATP concentrations were either 5,20 or 5Omicromolar so that they were at or below the Km for ATP. The ATP concentrations used were as follows, 5M for assays of MKKI, SAPK3, SAPK4, GSK3I3, PRK2 CK2 20j.im for assays of iNK, SAPK2f3, MAPKAP-K2, MSK1, PRAK, PKA, PKCa, PDKI, SGK, p7OS6K, ROCK-H, CHKI, CHK2, CSK, CDK2, and 5OpM for assays of SAPK2a, MAPK2IERK2, AMPK, LCK, P11K and MAPKAP-K1f3.
The following kinases were assayed against the substrates indicated.
Aurora B was assayed against the substrate peptide LRRLSLGLRRLSLGLRPJSLGLPJJSLG (300j.tM), ERK8 and MST-2 were both assayed against MBP (O.33mg/ml). IKK was assayed against the substrate peptide LDDRHDSGLDSMKDEEY (300i.tM), JNK3 was assayed against 3jtM ATF2[19-96J. MAPKAP-K3 and PKDI were both assayed against KKLNRTLSVA (30.tM), MARK3 was assayed against CI-IKtide (KKKVSRSGLYRSPSMpENLNppR) substrate peptide (300tM). MNK1 and MNK2 were both assayed against eIF4E protein (O.Smg/ml). NEK7 was assayed against FLAKSFGSPNRAyKK (300MM), PIM2 was assayed against RSRHSSYPAGT (300MM), L\PH PKB3-S474D was assayed against Crosstide (30MM), PLKI was assayed against ISDELMDATFADQEAKKK (300MM).
PRK2 was assayed against Long S6 peptide, KEAKEKRQEQIAKRRRLSSLRSTSKSGGSQK (30MM), RSK2 was assayed against KKLNRTLSVA (30MM), SRC was assayed against cdc2 peptide, KVEKIGEGTYGVVYK (300MM) and SRPK1 was assayed against peptide RSRSRSRSRSRSRSR (300MM). All enzymes were diluted in 50mM Tris/1-ICI pH 7.5, 0.1mM EGTA, 1mg/mi BSA, 0.1% 13-mercaptoethanol buffer and assayed in an incubation containing 50mM Tris/J-ICI pH7.5, 0.1mM EGTA, 0.1% J3-mercaptoethanol, CAMK-1 (5-2OmU) diluted in 50mM Tris/HCI p1-I 7.5, 0.1mM EGTA, 1mg/mi BSA, 0.1% 13-mercaptoethanoi is assayed against substrate peptide YLRRRLSDSNF in an incubation containing 50mM Tris/HCI pH7.5, 0.1mM EGTA, 0.5mM CaCI2, 0.3MM calmodulin, 0.1% f3-mercaptoethanoi, 3 00MM substrate peptide, 10mM magnesium acetate and 0.05mM [33P-T-ATP] (SOO-l000cpmlpmole). EF2K (5-2OmU) diluted in 50mM Hepes pH6.6, 0.1% f3-mercaptoethanol, 1mg/mi BSA is assayed against a substrate peptide RKKFGESKTKTKEFL in an incubation containing 50mM Hepes pH6.6, 0.2mM CaCI2, 0.3MM Calmodulin, 0.05% b-mercaptoethariol, 300MM substrate peptide, 10mM magnesium acetate and 0.05mM [33P-y-ATP] (500-1 000cpmIpmole).
smMLCK (5-2OmU) diluted in 50mM Hepes pH7.5, 0.1mM EGTA, 1 mg.mI BSA, 0.1% f-mercaptoethanol is assayed against substrate peptide KKRPQRATSNVFA in an incubation containing 50mM Hepes pH7.5, 0.1mM EGTA, 5mM CaCI2, 1OMM calmodulin, 300MM substrate peptide, 10mM magnesium acetate and 0.05mM [33P-7-ATP] (500-1 000cpmlpmole).
MAPKAP-Kla (5-2OmU diluted in 20mM MOPS pH 7.5, 1mM EDTA, 0.01% Brij35, 5% glycerol, 0.1% 13-mercaptoethanoj, 1mg/mi BSA) is assayed against KKLNRTLSVA in a final volume of 25.5.il containing 50 mM Na-J3-glycerophosphate pH 7.5, 0.5mM EDTA, 30 MM substrate peptide, 10mM magnesium acetate and 0.05 mM {33P-j'ATPJ (50-1000 cpmlpmole) and incubated for 40 mm at room temperature.
NEK6 (5-20 mU diluted in 50mM Tris (p1-I 7.5), 0.1mM EGTA, 1mg/mi BSA, 0.1 %,3-Mercaptoethano1) is assayed against NEK6 peptide (FLAKSFGSPNPJYJ(JQ in a final volume of 25.Sj.tl containing 50mM Iris (pH 7.5), 0.1mM EGTA, 0.01% Brij, 0.1%, P-Mercaptoethanol, NEK6 peptide (0.3mM), 10mM magnesium acetate and 0.05mM [33P-ATP](5OO-1000 cpm/pmole) and incubated for 30 mm at room temperature.
5-2OmU of NEK2a (diluted in 50mM Tris (pH 7.5), 0.1mM EGTA, 1mg/mi BSA, 0.1 %,-Mercaptoethano1) is assayed against NEK2a peptide (RFRRSRRMI) in a final volume of 25.5j.ti containing 50mM Iris (pH 7.5), 0.1mM EGTA, 0.01% Brij, 0.1%, 13-Mercaptoethanoz, 300MM NEK2a peptide, 10 mM magnesium acetate and 0.05 mM {33P-ATPJ(5oo-1ooo cpm/pmole) and incubated for 30 mins at room temperature.
IWH-PKBbeta-5474D (5-2OmU diluted in 50 mM Tris pH 7.5, 0.1 mM EGTA, 0.1% 13-mercaptoethanoj, 1 mg/mI BSA) is assayed against a modified Crosstide peptide (GRPRTSSFAEG}cJ() in a final volume of 25.5 M1 containing 50mM Tris pH 7.5, 0.05% 13-mercaptoethanol 30 MM substrate peptide, 10 mM magnesium acetate and 0.05 mM [33P-ATP] (50-1000 cpnilpmole) and incubated for 30 mm at room temperature.
Abbreviations Abbreviations used: AMPK, AMP-activated protein kinase; CAM-K, calmodulin-dependent protein kinase; CHK, checkpoint kinase; CK2, casein kinase 2; CREB, CAMP-response element binding protein; CSK, C-terminal Src kinase; DYRK, dual-specificity, tyrosine-phosphorylated and regulated kinase; EF2K elongation factor 2 kinase; EGF, epidermal growth factor; eIF4E eukaryotic initiation factor 4E; ERK, extracellular-signal-regujated kinase; GSK3, glycogen synthase kinase 3; IKKI3.j kappa B kinase; JNK, c-Jun N-terminal kinase; LCK, lymphocyte kinase; MAPK, mitogen-activated protein kinase; MAPKAP-K1, MAPK-activated protein kinase-1; MAPKAP-K2, MAPK-activated protein kinase 2; MKK, MAPK kinase (also called MEK); MLCK, myosin light chain kinase; MNK, MAPK-integrating kinase; MSK1, mitogen-and stress-activated protein kinase 1; NEK, never in mitosis gene a related protein kinase; PDK1, 3-phosphoinositide-dependent protein kinase 1; PKA, CAMP-dependent protein kinase; PKB, protein kinase B (also called Akt); PKC, protein kinase C; PKG, cGMP-dependent protein kinase; PHK, phosphorylase kinase; PLK, polo-like kinase 1; PRAK, p38-regulatcd/activated kinase; PRK, protein kinase C-related protein kinase; ROCKII, Rho-dependent protein kinase II; RSK2, ribosomal S6 kinase 2;SAPK2a, stress-activated protein kinase 2a (also called p38); SAPK2b, stress-activated protein kinase 2b (also called p382); SAPK3, stress-activated protein kinase 3 (also called p38y); SAPK4, stress-activated protein kinase 4 (also called p38ö); SGK, serum-and gIucocorticoicf-jndue kinase; SRC, v-src sarcoma viral oncogene homologue kinase; SRPKI, serine arginine protein kinase 1; p7OS6K, p70 ribosomal protein S6 kinase; Sk, skeletal muscle; Sm, smooth muscle.
Example 1: Expression and purification of GST-DYRKIa Flasks containing 500 ml of LB ampicillin are inoculated with pGEX-DYRKIa and grown at 37 C until OD at 600 nm is between 0.4 -0.6. The culture was then induced with 100 M JPTG and grown for 14 hours at 26 C.
The culture was harvested by centrifligation at 4,200 rpm for 30 mins and the bacterial pellet resuspended in ice cold lysis buffer (1 5 ml per IL of harvested culture) containing Roche protease inhibitor tablets (one tablet per 25 ml of lysis buffer).
The sample was then sonicated on ice for 8 x 15 seconds bursts, before being centrifuged at 15,000 rpm for 30 mins.
The clarified lysate was then added to GSH-Sepharose (Pharamacia) [which had been equilibrated in equilibration buffer] and end over end mixed for minutes at 4 C.
The GSH-Sepharose was then washed with wash buffer until the OD at 595 nm was zero.
GST-DYRKIa was eluted from the resin using elution buffer and fractions containing protein are pooled and dialysed overnight into dialysis buffer.
Buffers for purification of GST-DYRX1a Lysis Buffer: 50 mM Tris/FICI pH7.5 150mM NaCJ 1% Triton 1 mM EDTA 1 mM EGTA 0.1% t3-Mercaptoethanol 0.2 mM PMSF 1 mM benzamidjne Equilibration Buffer/Wash Buffer: 50 mM Tris pH7.5 250 mM NaC1 0.03% Brij-35 0.1mM EGTA 0.1 % 3-Mercaptoethanol 0.2 mM PMSF 1 mM benzamidine Elution: Wash buffer + 20mM glutathione (re-pl-I to 7.5) Dialysis: 50mM TrisfHCl pH7.5 0.1mM EGTA 150mM NaCI 50% glycerol 0.03% Brij-35 0.07% 13-Mercaptoethanol 1mM Benzamjdine 0.1mM PMSF.
Example 2: Kinase inhibition assays DYRK1A 33P screening assay: DYRK1A (5 -20 mU of diluted in 50 mM Iris pH 7.5, 0.1 mM EGIA) was assayed against Woodtide (KKISGRLSPIMTEQ) in a final volume of 25.5.tl containing 50 mM Iris pH 7.5, 0.1 mM EGTA, 350 uM substrate peptide, 10 mM magnesium acetate and 0.5 pi inhibitor and incubated at room temperature for 5 mins, followed by the addition of 0.05 mM [33P-gamma-ATP] (50-1000 cpm/pmole) and incubated for 30 mins at room temperature. Assays were stopped by addition of 5 jtt of 0.5 M (3%) orthophosphoric acid then harvested onto P81 Unifilter plates with a wash buffer of 50 mM orthophosphoric acid. Filterplates were then air dried overnight. I 0il of Microscint 0 was added per well prior to counting for radioactivity.
DYR2 and DYRK3 were assayed in an analogous manner to that described above for DYRK1a.
Harmine, 1-larmaline, Harmane and Harmalol were tested at 1 M and 10 uM (in the assay).
Results are shown in Tables I and 2 where values represent the percent activity in relation to the activity obtained in the absence of inhibitor, can be seen that all three compounds are very specific and active at 10gM and that harmine is a very potent and specific inhibitor of DYRKIa and still shows a high degree of activity at a concentration of 1.tM.
1C50 values were also obtained for DYRK1a, 2 and 3 with harmine (ATP at 50gM) (i.e. the concentration of the inhibitor that is required to provide 50% inhibition of the enzyme. The results are as follows: DYRKIa 1C50 O.08itM DYRK2 1C50 O.9i.tM DYRK3 1C50 O.8p.tM.
The 1C50 values were calculated by using half log dilutions of inhibitor, starting at I OOtM..
TABLE I
Legend Activities are presented as a percentage of those obtained in control assays carried out in the absence of inhibitor
TABLE 1
Harmaljne Harmane Harmalol Harmjne Concentration iM) 1 +1-SE 1 +1-SE 1 +1-SE -1 +1-SE MKKI 4 5 97 3 92 7 -76 3 JNKJSAPK1c 99 -6 96 -4 87 2 85 11 JNK3 8' 3 75 2 92 5 89 ______ SAPK2aJp38 89 6 95 5 95 _______ 95 5 SAPK2b/p3 8132 91 6 90 7 88 4 94 5 SAPK3/p38g 98 -0 108 4 98 9 82 -3 SAPK4/p38d 76 3 94 6 101 0 96 7 MAPK2/E1jç -80 2 86 7 88 3 98 2 ERK8 -58 2 39 3 41 2 25 1 MAPKAP-KJa 98 0 92 3 101 5 105 -6 MAPKAP-KIb 87 2 83_ 7 87 1 89 0 MAPKAP-K2 104 3 -114 -3 79 4 78 6 MAPKAP-K3 79 -3 85 3 95 1 89 -4 MSK1 98 ______ 5 98 1 84 3 90 ______ MNK1 I 89 6 871 O 8ü 1 84 -3 MNK2 88 0 75 9 97 6 84 0 PRAK 88 1 80 2 84 8 81 2 PKA 70 0 80 4 90 2 82 2 PKCa 88 2 84 1 109 0 96 0 PDK1 100 1 86 0 88 1 89 2 PKBtph 80 2 83 1 92 6 107 3 PKBb 97 3 92 6 103 3 94 1 SGK 14 1 98 2 62 4 66 1 CAMK-1 99 2 108 2 93 7 107 1 smMLCK 92 3 93 8 76 4 88 1 EFK2 106 9 96 3 97 9 102 1 70S6K 71 2 81 4 95 3 90 6 GSK3b 77 5 99 0 90 4 82 7 ROCK-H _____ 99 0 80 1 96 4 84 7 PRIQ 97 1 79 2 86 6 82 0 AMPK 97 3 75 5 92 1 98 1 CHK1 78 9 118 5 93 1 86 4 CHK2 89 0 89 4 76 5 78 6 CK1 84 2 82 1 83 1 61 4 CK2 94 4 96 3 55 7 82 8 PHK 73 9 94 6 101 ________O 103 5 Lel 77 4 92 5 85 2 92 2 CSK 64 3 92 1 110 2 92 1 Src 47 0 -106 0 101 0 108 2 CDK2/cyclin A 99 9 -110 3 9 5 98 5 DYRKIa 78 5 39 5 25 1 4 0 IEK2a 69 3 103 2 104 6 106 11 EK6 99 5 87 4 94 4 96 0 NEK7 95 3 -100 4 83 0 90 6 IKKb 78 1 90 7 93 1 97 8 PIM2 86 5 87 6 90 7 77 2 SRPK1 104 5 100 5 88 0 86 ________ Aurora B 98 0 98 1 110 3 100 9 MARK3 99 1 -108 5 93 7 86 1 MST2 98 4 116 5 85 5 91 5 PKD1 9 5 103 6 75 3 86 3 _____________________ 92 4 109 6 88 8 92 4
TABLE 2
Harmaljne Harmane Harmalol Harmine +1-SE 10 +1-SE 10 +1-SE 10 +1-SE MKKI 39 3 97 166 6 73 4 JNKJSAPK1c -96 3 72 3 84 6 69 7 JNK3 81 _______ 74 2 94 4 83 1 SAPK2aJp38 86 1 95 3 74 2 81 5 SAPK2b/p38f32 93 4 107 4 79 1 87 3 SAPK3/p38g 94 3 92 2 92 8 72 5 SAPK4/p38d 113 7 101 3 93 1 82 2 MAPK2/ERK2 89 4 93 1 85 3 89 5 ERK8 21 2 28 1 21 1 19 1 MAPKAP-KIa 90 1 95 4 85 5 92 1 MAPKAP-KJb 80 1 87 4 67 1 95 4 MAPKAP-K2 112 2 111 9 69 1 82 5 MAPKAP-K3 82 2 84 2 88 5 93 1 MSK1 111 1 85_ 259 9 88 3 MNKI 82J 2 69 748 4 52 1 MNK2 77 1 66 9 71 8 98 1 PRAK 93 2 84 1 78 1 75 3 PKA 86 1 89 175 5 92 2 PKCa 81 0 93 6 78 1 101 1 PDKI 95 0 103 2 96 1 95 1 PKBph 98 5 95 5 58 3 107 7 PKBb 96 8 97 3 77 4 101 7 SGK 84 6 112 3 45 8 62 3 CAMK-1 110 1 99 2 60 2 94 8 smMLCK 104 6 97 6 71 2 76 6 EFK2 100 1 90 9 85 1 101 0 S6K 83 3 87 2 69 5 93 9 GSK3b 82 7 91 2 73 5 72 1 ROCK-Il 81 0 64 6 81 1 61 6 PRK2 ____ 83 3 48 2 54 7 45 0 AMPK 83 2 86 4 52 3 103 4 CHK1 67 6 110 7 81 7 86 5 CHK2 89 3 87 5 57 5 79 6 CKI 65 5 73 5 48 2 21 2 CK2 88 1 61 3 12 141 9 PHK 88 8 86 3 63 9 82 2 Lck 87 2 98 4 68 4 91 5 CSK 90 1 107 6 92 1 101 9 Src 65 5 105 3 83 0 98 6 CDK2/cyclin A 98 5 82 4 77 5 62 9 DYRKIa 8 2 ii 1 3 0 1 1 EK2a 109 2 106 0 83 5 111 7 EK6 87 5 94 7 92 1 99 2 NEK7 115 6 96 2 56 9 92 2 IKKb 82 5 76 2 69 5 73 1 PIM2 101 4 78 3 57 0 41 1 SRPKI 97 3 105 5 72 11 83 6 Aurora B 112 1 96 3 83 6 102 1 MARK3 103 6 97 8 84 5 86 1 MST2 105 3 108 2 74 1 81 1 PKD1 101 5 71 4 21 4 53 6 PLK1 100 9 128 4 81 4 87 3

Claims (12)

  1. Claims I. Use of a compound or salt or hydroxide thereof of the
    following formula (1) wherein R1 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxy, alkylthjo, alkyloxycarbonyl; hydroxyl; nitro; amino; halo or oxo; R2 and R3 are independently selected from hydrogen; substituted or unsubstituted C,-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino or halo; and R4 is selected from hydrogen; substituted or unsubstituted C,-C6 alkyl, alkenyl, or alkyloxycarbonyl; the dashed line represents a single or double bond, for the manufacture of a medicament for alleviating or minimising a symptom or condition observed in a Down's syndrome subject.
  2. 2. The use of claim 1, wherein the compound is administered to a Down's syndrome subject from birth, or soon thereafter, until adolescence or possibly into and during adulthood.
  3. 3. The use of any preceding claim, wherein R1, R2 and R3 are independently selected from hydrogen, hydroxyl or C1-C6 alkyl or alkyloxy; and R4 is selected from hydrogen or C1-C6 alkyl.
  4. 4. The use of any preceding claim, wherein the salts are formed by preparing a quatemary ammonium salt at one or more of the nitrogen atoms.
  5. 5. The use of any preceding claim, wherein the compounds are selected from the group consisting of: (i) Harmine, where R1 is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a double bond; (ii) Harmaline, where R1 is H, R2 is CH3, R3 is OCR3, R4 is H and the dashed line is a single bond; (iii) Harmane, where R1 is H, R2 is Cl-I3, R3 is H, R4 is H and the dashed line is a double bond; and (iv) Harmalol, where R1 is H, R2 is CH3, R3 is OH, R is H and the dashed line is a single bond.
  6. 6. A pharmaceutical formulation, comprising a compound or physiologically acceptable salt, hydroxide or other physiologically functional derivative thereof, of the following formula (1) wherein R1 is selected from hydrogen; substituted or unsubstituted Cj-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino; halo or oxo; R2 and R3 are independently selected from hydrogen; substituted or unsubstituted C-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino or halo; and R1 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxycarbonyl; the dashed line represents a single or double bond, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic andlor prophylactic ingredients.
  7. 7. The pharmaceutical formulation of claim 6, wherein R1, R2 and R3 are independently selected from hydrogen, hydroxyl or C1-C6 alkyl or alkyloxy; and R4 is selected from hydrogen or C1-C6 alkyl.
  8. 8. The pharmaceutical formulation of claims 6 or 7, wherein the salts are formed by preparing a quaternary animonium salt at one or more of the nitrogen atoms.
  9. 9. The pharmaceutical formulation of claims 6, 7 or 8, wherein the compounds are selected from the group consisting of: (i) Harmine, where R is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a double bond; (ii) Harmaljne, where R1 is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a single bond; (iii) Harrnane, where R1 is H, R2 is CH3, R3 is H, R4 is 1-I and the dashed line is a double bond; and (iv) Harmalol, where R1 is H, R2 is Cl-I3, R3 is OH, R4 is H and the dashed line is a single bond.
  10. 10. The pharmaceutical formulation of any of claims 6-9, suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and/or pulmonary administration e.g., by inhalation.
  11. 11. The pharmaceutical formulation of claim 10, wherein when suitable for pulmonary administration via the buccal cavity, particles containing an active compound have a diameter in the range of 0.5 to 7 microns and are delivered to the bronchial tree of the recipient.
  12. 12. The use of claim 1-5 or formulation of claim 6-Il, wherein the dosage of the compound is sufficient to alleviate or minimise a symptom or condition observed in a Down's syndrome subject, whilst not eliciting an hallucinogenic effect on the subject.
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