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WO2009036768A2 - Diagnostic de la prise de poids potentielle chez un sujet - Google Patents

Diagnostic de la prise de poids potentielle chez un sujet Download PDF

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Publication number
WO2009036768A2
WO2009036768A2 PCT/DK2008/050227 DK2008050227W WO2009036768A2 WO 2009036768 A2 WO2009036768 A2 WO 2009036768A2 DK 2008050227 W DK2008050227 W DK 2008050227W WO 2009036768 A2 WO2009036768 A2 WO 2009036768A2
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Prior art keywords
agent
pi3k delta
subject
disorder
delta activity
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PCT/DK2008/050227
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English (en)
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WO2009036768A3 (fr
Inventor
Benny Bang-Andersen
John Nicholas Pearson
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H. Lundbeck A/S
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Publication of WO2009036768A2 publication Critical patent/WO2009036768A2/fr
Publication of WO2009036768A3 publication Critical patent/WO2009036768A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • G01N2333/91205—Phosphotransferases in general
    • G01N2333/9121—Phosphotransferases in general with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases
    • G01N2333/91215—Phosphotransferases in general with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases with a definite EC number (2.7.1.-)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity

Definitions

  • the present invention relates to a method for diagnosing or prognosing potential metabolic syndrome in a subject.
  • the present invention further relates to a method for diagnosing or prognosing potential metabolic syndrome in a subject, which can be induced by medication.
  • the present invention further relates to use of an agent in the manufacture of a medicament for treating a disorder or a disease in a subject.
  • the present invention further relates to an agent for use in a method for treating a disorder or a disease in a subject.
  • the present invention further relates to a method for treating a disorder or a disease in a subject comprising administering a therapeutically effective amount of an agent to a subject.
  • the present invention further relates to a method for identifying an anti-psychotic compound.
  • Schizophrenia is distinguished from other psychotic disorders based on a characteristic cluster of symptoms, namely positive symptoms (i.e. delusion, hallucinations, disorganised thinking, disorganised behaviour and catatonia), negative symptoms (i.e. affective flattening, poverty of speech and an inability to initiate and persist in goal-directed activities), and cognitive symptoms (i.e. impairment of memory, executive function and attention).
  • positive symptoms i.e. delusion, hallucinations, disorganised thinking, disorganised behaviour and catatonia
  • negative symptoms i.e. affective flattening, poverty of speech and an inability to initiate and persist in goal-directed activities
  • cognitive symptoms i.e. impairment of memory, executive function and attention.
  • the antipsychotic drugs are divided into classical and atypical APDs.
  • the classical APDs were discovered in the 1950s with chlorpromazine as the first prominent example, whereas the atypical APDs were introduced into the treatment of schizophrenia during the 1990s with clozapine as the first example.
  • the term classical APD is linked to compounds that show effect in the treatment of positive symptoms (psychotic symptoms) at similar doses that induce extrapyramidal symptoms (EPS, i.e. parkinsonian symptoms, dystonia, akathisia and tardive dyskinesia).
  • EPS extrapyramidal symptoms
  • the classical APDs are also without effect on negative and cognitive symptoms, and it is generally agreed that these drugs may even worsen these symptoms. It has been argued that the worsening of negative and cognitive symptoms by classical APDs may be a consequence of their EPS, and the separation of the dose-response curves for antipsychotic effect and EPS is the foremost important property of the atypical APDs.
  • the term atypical APD is linked to a diverse group of drugs having antipsychotic effect at doses not giving EPS.
  • All the APDs display some level of dopamine D 2 antagonism (besides from aripiprazole displaying D 2 partial agonism) but also agonism/antagonism/inverse agonism at a number of additional receptors/sites (e.g. 5-HT 2 A, 5-HT 2 c, H 1 , etc) specific for each of the compounds.
  • additional receptors/sites e.g. 5-HT 2 A, 5-HT 2 c, H 1 , etc
  • APDs have their own compound specific advantages but also limitations, such as for example anticholinergic and antihistaminergic side effects, a tendency to prolong the QT interval and/or to increase weight.
  • clozapine and olanzapine have been linked to weight gain and metabolic side effects, such as e.g. insulin resistance.
  • Olanzapine and clozapine have been associated with substantial weight gain in patients. Indeed, some patients have added over 30 kg after commencement of medication. In a recent extensive summary of the clinical data available for APDs, it was found that on average olanzapine and clozapine induced a 4 - 4.5 kg weight gain after 10 weeks medication. Other compounds such as quetiapine, chlorprothixene and thioridazine induced a weight gain of 2-3 kg over 10 weeks. Risperidone has been shown to induce a minor weight gain of up to 2 kg whilst no weight gain was observed for ziprasidone (Allison et al, 1999, Am J Psychiatry 156: 1686-1696). The weight gain associated with olanzapine has been attributed to increased food intake with an increase in peripheral fat (increased adiposity) (Eder et al., 2001, Am J Psychiatry 158:1719-1722).
  • Weight gain or diabetes induced by medication are of major concern for obvious health reasons.
  • the threat of weight gain (obesity) or diabetes in patients suffering other conditions or disorders, such as hypertension and heart disease are of even greater concern.
  • the side effect can be life threatening.
  • PBK delta (PIK3CD, EC 2.7.1.153 located on Chromosome 1 at Ip36.22) is inhibited by APDs, an inhibition that is correlated with the weight gain, which has been observed in patients taking these APDs.
  • the present invention relates to a method for diagnosing or prognosing potential metabolic syndrome in a subject, comprising the step of analyzing a sample from said subject for PI3K delta activity.
  • the present invention relates to a method for diagnosing or prognosing potential metabolic syndrome in a subject, which can be induced by medication, comprising the steps i) analyzing a sample from said subject for PI3K delta activity before said medication; ii) analyzing a sample from said subject for PI3K delta activity after medication.
  • the present invention relates to use of an agent in the manufacture of a medicament for treating a disorder or a disease in a subject, characterized in that the PI3K delta activity in said subject has been measured to be about normal or higher than normal.
  • the present invention relates to an agent for use in a method for treating a disorder or disease in a subject, characterized in that the PBK delta activity in said subject has been measured to be about normal or higher than normal.
  • the present invention relates to a method for treating a disorder or a disease in a subject comprising administering a therapeutically effective amount of an agent to a subject, characterized in that the PBK delta activity in said subject has been measured to be about normal or higher than normal.
  • the present invention relates to a method for identifying an anti-psychotic compound comprising the steps of:
  • PBKdelta is responsible for glycogen inhibition in muscle cells and that specific inhibitors of PBK delta will inhibit glycogen content of these cells in a similar manner to 2-(6-Amino- purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one.
  • Y-axis relative glycogen content.
  • X-axis concentration ( ⁇ M).
  • weight gain associated with the use of antipsychotic medication can be ascribed to PBK delta activity.
  • olanzapine, clozapine and other APDs selectively inhibit PBK delta to varying degrees but not any other isoform, such as alpha, beta or gamma.
  • the degree of inhibition, together with the bio distribution, such as accumulation of the compound in the muscles, reflects the degree of glycogen synthesis inhibition.
  • APDs directly and specifically inhibit human delta isoform of phosphoinositide kinase (PBK delta or PIK3CD, EC 2.7.1.153), one of the first kinases in the insulin-signaling phosphorylation cascade but not any other isoform, such as alpha, beta or gamma.
  • PBK delta or PIK3CD, EC 2.7.1.153 human delta isoform of phosphoinositide kinase
  • glycogen is formed from glucose when insulin stimulates the insulin receptor located on the plasma membrane of cells.
  • a complex of proteins associated with the insulin receptor include PB kinases (isoforms alpha, beta, gamma and delta) and they, upon stimulation, phosphorylate the membrane bound phosphatidylinositol 3,4-triphosphate (PIP 2 ) to form phosphate- idylinositol 3,4,5-triphosphate (PIP 3 ). Once formed, PIP 3 recruits PDKl and PKB/AKTl to the membrane to form a complex that then phosphorylates GSK3 beta.
  • PB kinases isoforms alpha, beta, gamma and delta
  • Phospho-GSK3 beta is inactive and can no longer phosphorylate Glycogen Synthase enzyme (phosphor glycogen synthase is inactive and unable to synthesize glycogen) Thus, with insulin stimulation, glycogen synthesis is activated (see Cross et al., 1995 Nature 378: 785-789).
  • the APDs selectively inhibit PBK delta and not any of the other isoform, such as alpha, beta or gamma.
  • the degree of inhibition varies from an IC 50 of 10-50 ⁇ M.
  • PBK delta is heavily expressed in leukocytes (Chantry et al. 1997, J Biol Chem. 31:19236-19241), but also expressed in numerous other tissues including skeletal muscles (Seki et al. 1997, DNA Res. 4:355-358).
  • the alpha isoform of PBK is the main PB kinase regulating glycogen formation in the liver (Carpenter et al., 1990, J. Biol. Chem. 265: 19704-19711 (1990).
  • APDs are involved in glycogen depletion in muscles cells (Engl et al., 2005, Molecular Psychiatry, 10:1089-1096). Excess glucose from the muscles, normally destined for glycogen synthesis, is postulated to re-enter the blood stream where it is directed to the adipocytes and deposited as fat. Patients receiving APDs have been noted for their disregulation of serum glucose (Dwyer et al., 2001, Ann Clin Psych, 13:103-113).
  • APDs were recently shown to induce the expression of AMP -kinase in the brain and this is a vital enzyme involved in appetite regulation (Kim et al., 2007, PNAS, 104: 3456-3459).
  • AMP-kinase expressed in the muscles and brain, is usually associated with and recognizes glycogen reserves (Polekhina et al., 2005, Structure, 13:1453-1462).
  • One of the functions of this kinase is to sense energy levels and it is directly involved in appetite regulation.
  • Weight gain can be predicted by measuring PI3K delta activity (for method to measure PIK3 delta activity, see Gray et al., 2003 Anal. Biochem. 313:234-245) and the formation of glycogen. More specifically, this can be achieved by measuring the activity of the enzyme from tissue samples of medicated patients or the level of the products of PI3K delta.
  • activity of PI3K delta can be determined in blood samples or muscle biopsies by one of the following methods: the enzymatic formation of phosphatidylinositol 3,4,5-triphosphate (PIP3) or of a analogous product or PI3K delta inhibition can be determined by the cellular levels of protein PIP3 in cells relative to known control samples either via standard western blot analysis with antibodies directed specifically to PIP3 or via a fluorescently labelled marker of PIP3.
  • PIP3 phosphatidylinositol 3,4,5-triphosphate
  • PI3K delta inhibition can also be measured indirectly by measuring the cellular levels of phosphorylated AKTl protein relative to known controls; likewise, PI3K delta inhibition can be measured by the cellular levels of phosphorylated GSK3 beta protein relative to known controls; PI3K delta inhibition can also be measured by the cellular levels of phosphorylated glycogen synthase protein relative to known controls.
  • PI3K delta inhibition can also be measured indirectly by the amounts of glycogen in blood or tissue to known controls. This can be measured either by elimination of free glucose followed by digestion of glycogen and subsequent measure of released glucose. Glycogen can also be quantitated in tissue with Periodic acid- S chiff staining or similar techniques.
  • PBK delta inhibition can also be predicted by comparing the exposure level in muscles of a specific compound with a known IC50 for PBK delta.
  • the distribution of compound in the muscles and elsewhere in the body can be determined either directly by taking biopsies and determining compound concentration using normal techniques or indirectly by supplying the patient with radio-labelled compound and following its movement through out the body. Calculation of compound concentration can be used to determine the likely extent of inhibition of PBK delta and probability of weight gain
  • biological sample is intended to include tissues, cells, biological fluids, such as blood, and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject.
  • Phosphoinositide kinase delta isoform refers to a human protein also known as phosphor- inositide-3-kinase, catalytic, delta polypeptide or a number of other synonyms (pi IOdelta, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform, PBK, PB- kinase pi 10 subunit delta, PtdIns-3 -kinase, pi 10).
  • the reference DNA sequence is NM_005026 and the protein NP_005017.3.
  • PBK delta activity in said subject refers to the situation wherein the PBK delta activity in said subject is about the same in relation to expression and activity of PBK delta of the general population.
  • the term "subject” refers to any warm-blooded species such as human and animal.
  • the subject, such as a human, to be treated or diagnosed according to the present invention may in fact be any subject of the human population, male or female, which may be divided into children, adults, or elderly. Any one of these patient groups relates to an embodiment of the invention.
  • treating refers to preventing or delaying the appearance of clinical symptoms of a disease or condition in a subject that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition.
  • Treating also refers to inhibiting the disease or condition, i.e., arresting or reducing its development or at least one clinical or subclinical symptom thereof.
  • Treating or “treatment” further refers to relieving the disease or condition, i.e., causing regression of the disease or condition or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject and/or the physician. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate embodiments of the invention.
  • diagnosing refers to identifying a disorder or a disease in a subject or the susceptibility of a subject to the disorder of the present invention (e.g., a predisposition to develop a disorder).
  • metabolic syndrome refers to a variety of disorders comprising glucose intolerance/insulin resistance, type 2 diabetes, arterial hypertension, dyslipidaemia and obesity.
  • the term "pharmaceutically acceptable” refers to molecular entities and compositions that are "generally regarded as safe” - e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human.
  • this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • CNS-disorder refers to a disorder of the central nervous system (CNS).
  • anti CNS-disorder agent refers to a medicament approved for the treatment of CNS-disorder.
  • the term "effective amount” refers to the amount/dose of a compound or pharmaceutical composition that is sufficient to produce an effective response (i.e., a biological or medical response of a tissue, system, animal or human sought by a researcher, veterinarian, medical doctor or other clinician) upon administration to a subject.
  • the "effective amount” will vary depending on inter alia the disease and its severity, and the age, weight, physical condition and responsiveness of the subject to be treated.
  • agent refers to a substance selected from the group that includes, but is not limited to, proteins, peptides or amino acids; antibodies or fragments thereof; nucleic acids such as DNA, such as full-length genes or fragments thereof derived from genomic, cDNA or artificial coding sequences, gene regulatory elements, RNA, including mRNA, tRNA, ribosomal RNA, ribozymes and antisense RNA, oligonucleotides and oligoribonucleotides, deoxyribonucleotides and ribonucleotides; carbohydrates; lipids; proteoglycans; organic molecules such as small molecules; inorganic molecules.
  • the present invention relates to a method for diagnosing or prognosing potential metabolic syndrome in a subject, comprising the step of analyzing a sample from said subject for PBK delta activity.
  • the potential metabolic syndrome is potential weight gain.
  • said sample is a biological sample.
  • the PBK delta activity is measured directly.
  • the PBK delta activity is measured by enzymatic formation of PIP3 or of an analogous product, or by western blot analysis with antibodies directed specifically to PIP3, or with a fluorescently labelled marker of PIP3.
  • PBK delta activity is measured indirectly.
  • the PBK delta activity is measured by measuring cellular levels of phosphorylated AKTl or GSK3 beta, or by measuring cellular levels of phosphorylated glycogen synthase protein, or by measuring cellular levels of PBK delta mRNA or PBK delta protein, or by measuring the amounts of glycogen in blood or tissue.
  • the subject is a human.
  • the present invention relates to a method for diagnosing or prognosing potential metabolic syndrome in a subject, which can be induced by medication, comprising the steps i) analyzing a sample from said subject for PBK delta activity before said medication; ii) analyzing a sample from said subject for PBK delta activity after medication.
  • the potential metabolic syndrome is potential weight gain.
  • step ii) is performed when medication has reached steady-state.
  • step ii) is performed after a period of time equivalent to about 5-9 half lives of said medication, such as about 5, 6, 7, 8 or 9 half lives of said medication.
  • said sample is a biological sample.
  • the PBK delta activity is measured directly.
  • the PBK delta activity is measured by enzymatic formation of PIP3 or of an analogous product, or by western blot analysis with antibodies directed specifically to PIP3, or with a fluorescently labelled marker of PIP3.
  • PBK delta activity is measured indirectly.
  • the PBK delta activity is measured by measuring cellular levels of phosphorylated AKTl or GSK3 beta, or by measuring cellular levels of phosphorylated glycogen synthase protein, or by measuring cellular levels of PBK delta mRNA or PBK delta protein, or by measuring the amounts of glycogen in blood or tissue.
  • said medication is anti-psychotic medication.
  • the anti-psychotic medication is selected from olanzapine, clozapine, quetiapine, ziprasidone or a pharmaceutically acceptable salt thereof.
  • said medication is anti-depressant medication.
  • the antidepressant medication is selected from amitriptyline or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • the present invention relates to use of an agent in the manufacture of a medicament for treating a disorder or a disease in a subject, characterized in that the PBK delta activity in said subject has been measured to be about normal or higher than normal.
  • said agent is an anti CNS-disorder agent.
  • said disorder is a CNS- disorder.
  • the CNS-disorder is psychosis or schizo- phrenia and the anti CNS-disorder agent is an antipsychotic agent.
  • the CNS-disorder is depression and the anti CNS- disorder agent is an anti-depressant agent.
  • the anti-psychotic agent is selected from olanzapine, clozapine, quetiapine, ziprasidone or a pharmaceutically acceptable salt thereof.
  • the anti-depressant agent is selected from amitriptyline or a pharmaceutically acceptable salt thereof.
  • the PBK delta activity is determined by analyzing a biological sample from a subject. In another embodiment of the third aspect of the invention the PBK delta activity is measured directly.
  • the PBK delta activity is measured by enzymatic formation of PIP3 or of an analogous product, or by western blot analysis with antibodies directed specifically to PIP3, or with a fluorescently labelled marker of PIP3.
  • PBK delta activity is measured indirectly.
  • the PBK delta activity is measured by measuring cellular levels of phosphorylated AKTl or GSK3 beta, or by measuring cellular levels of phosphorylated glycogen synthase protein, or by measuring cellular levels of PBK delta mRNA or PBK delta protein, or by measuring the amounts of glycogen in blood or tissue.
  • the subject is a human.
  • the present invention relates to an agent for use in a method for treating a disorder or disease in a subject, characterized in that the PBK delta activity in said subject has been measured to be about normal or higher than normal.
  • said agent is an anti CNS-disorder agent.
  • said disorder is a CNS-disorder.
  • the CNS-disorder is psychosis or schizophrenia and the anti CNS-disorder agent is an antipsychotic agent.
  • the CNS-disorder is depression and the anti CNS- disorder agent is an anti-depressant agent.
  • the anti-psychotic agent is selected from olanzapine, clozapine, quetiapine, ziprasidone or a pharmaceutically acceptable salt thereof.
  • the anti-depressant agent is selected from amitriptyline or a pharmaceutically acceptable salt thereof.
  • the PBK delta activity is determined by analyzing a biological sample from a subject. In another embodiment of the fourth aspect of the invention the PBK delta activity is measured directly.
  • the PBK delta activity is measured by enzymatic formation of PIP3 or of an analogous product, or by western blot analysis with antibodies directed specifically to PIP3, or with a fluorescently labelled marker of PIP3.
  • PBK delta activity is measured indirectly.
  • the PBK delta activity is measured by measuring cellular levels of phosphorylated AKTl or GSK3 beta, or by measuring cellular levels of phosphorylated glycogen synthase protein, or by measuring cellular levels of PBK delta mRNA or PBK delta protein, or by measuring the amounts of glycogen in blood or tissue.
  • the subject is a human.
  • the present invention relates to a method for treating a disorder or a disease in a subject comprising administering a therapeutically effective amount of an agent to a subject, characterized in that the PBK delta activity in said subject has been measured to be about normal or higher than normal.
  • said agent is an anti CNS-disorder agent.
  • said disorder is a CNS-disorder.
  • the CNS-disorder is psychosis or schizophrenia and the anti CNS-disorder agent is an antipsychotic agent.
  • the CNS- disorder is depression and the anti CNS-disorder agent is an anti-depressant agent.
  • the anti-psychotic agent is selected from olanzapine, clozapine, quetiapine, ziprasidone or a pharmaceutically acceptable salt thereof.
  • the anti-depressant agent is selected from amitriptyline or a pharmaceutically acceptable salt thereof.
  • the PBK delta activity is determined by analyzing a biological sample from a subject. In another embodiment of the fifth aspect of the invention the PBK delta activity is measured directly.
  • the PBK delta activity is measured by enzymatic formation of PIP3 or of an analogous product, or by western blot analysis with antibodies directed specifically to PIP3, or with a fluorescently labelled marker of PIP3.
  • PI3K delta activity is measured indirectly.
  • the PI3K delta activity is measured by measuring cellular levels of phosphorylated AKTl or GSK3 beta, or by measuring cellular levels of phosphorylated glycogen synthase protein, or by measuring cellular levels of PI3K delta mRNA or PI3K delta protein, or by measuring the amounts of glycogen in blood or tissue.
  • the subject is a human.
  • the present invention relates to a method for identifying an anti-psychotic compound comprising the steps of:
  • said target by interaction with said compound will mediate an effect that can treat and/or prevent psychosis, or ameliorate the symptoms of psychosis.
  • said compound when tested for inhibition of PI3K delta activity does not inhibit said PI3K delta activity.
  • said method further comprises the step of measuring the bio-distribution of said compound.
  • the present invention relates to the marketing of a medicinal product comprising a compound for treating a disease or a disorder in a subject, said marketing comprising the public spreading of the information that the PI3K delta activity has an impact on potential metabolic syndrome of said subject.
  • said compound is an anti-psychotic compound for treating psychosis in a subject.
  • said potential metabolic syndrome is a potential weight gain of said subject.
  • the disorders that can be treated and diagnosed according to the present invention are known according to established and accepted classifications, which can be found in various sources.
  • DSM-IVTM Diagnostic and Statistical Manual of Mental Disorders
  • ICD-IO International Classification of Diseases, Tenth Revision
  • the unit dose is containing the active ingredient in an amount from about 10 ⁇ g/kg to 10mg/kg body weight, in another embodiment from about 25 ⁇ g/day/kg to 1.0 mg/day/kg, in yet another embodiment from about 0.1 mg/day/kg to 1.0 mg/day/kg body weight. In another embodiment, the unit dose is containing the active ingredient in an amount from 0.1 mg/day/kg to 1.0 mg/day/kg body weight.
  • the compounds mentioned above may be used as the base of the compound or as an acceptable acid addition salt thereof, such as a pharmaceutically acceptable acid addition salt thereof or as an anhydrate or hydrate of such salt.
  • the compounds mentioned above or a pharmaceutically acceptable salt thereof may be administered in any suitable way e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
  • the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
  • the compound of the invention is most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 10 ⁇ g/kg to 10mg/kg body weight, for example 25 ⁇ g/day/kg to 1.0 mg/day/kg.
  • unit dosage forms such as tablets or capsules
  • the active ingredient in an amount from about 10 ⁇ g/kg to 10mg/kg body weight, for example 25 ⁇ g/day/kg to 1.0 mg/day/kg.
  • Methods for the preparation of solid or liquid pharmaceutical preparations are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins (2005). Tablets may thus be prepared by mixing the active ingredients with an ordinary carrier, such as an adjuvant and/or diluent, and subsequently compressing the mixture in a tabletting machine.
  • Non-limiting examples of adjuvants and/or diluents include: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colourings, aroma, and preservatives may also be used provided that they are compatible with the active ingredients.
  • the pharmaceutical compositions of the invention thus typically comprise an effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • PIProfilerTM assay makes use of the specific, high affinity binding of the GRPl pleckstrin homology (PH) domain to PIP3, the product of the type I PI 3 -kinase acting on its physiological substrate PIP2.
  • PH GRPl pleckstrin homology
  • a sensor complex is formed involving a europium labeled anti-GST mAb, a GST tagged GRPl PH domain, biotinylated short chain PIP3 and Streptavidin-APC (allophycocyanin).
  • FRET fluorescence resonance energy transfer
  • the reaction was stopped with the addition of 5 ⁇ L stop solution (containing biotinylated-PIP3 and EDTA). 5 ⁇ l of Detection Buffer containing Europium labelled anti-GST monoclonal antibody, GST tagged GRPl PH domain, and Streptavidin Allophycocyanin was then added and time -resolved fluorescence (Ex 380, Em 660) determined.
  • a radiometric assay is used (ref).
  • the example shown here relates to GSK3 beta.
  • GSK3 beta In a final reaction volume of 25 ⁇ L, GSK3 beta (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20 ⁇ M YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (phospho GS2 peptide), 10 mM MgAcetate and [ ⁇ - 33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix.
  • the reaction is stopped by the addition of 5 ⁇ L of a 3% phosphoric acid solution. 10 ⁇ L of the reaction is then spotted onto a P30 filter mat and washed three times for 5 minutes in 50 mM phosphoric acid and once in methanol prior to drying and scintillation counting. Compound was added to the reaction at 10 and 100 ⁇ M final concentration and inhibition determined by reduced scintillation counts.
  • Table 1 shows that none of the selected atypical APDs inhibit the selected kinases of the insulin-signaling cascade. However, Table 2 and 3 show that atypical APDs selectively inhibit the delta isoform of PI3K, with an IC50 down to 11 ⁇ M.
  • PI3K delta is the enzyme responsible for controlling glycogen formation in muscles
  • 2-(6-Amino-purin- 9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one 2-(6-Amino-purin-9-ylmethyl)-5- methyl-3-o-tolyl-3H-quinazolin-4-one was prepared as described in US6667300 example D- 030. This compound was administered to human skeletal muscles cells (Lonza) cultured in 6-well plates and allowed to differentiate into myoblasts over an 5 day period once con- fluent.
  • the myoblasts were then dosed with varying concentrations of reference compound for one hour before the cells were given insulin (100 ng/ml) to stimulate glycogen formation (as described for rat mucle cells by Engl et al., 2005, Molecular Psychiatry, 10:1089-1096). After 3 hours, the cells were washed with phosphate-buffered saline solution then fixed with an acid paraformaldehyde solution. The cells were then subjected to Periodic acid-Schiff staining (strictly according to manufacture's protocol - Sigma cat no. 395B-1KT). Upon complete development of colouring, the cells were photographed in black & white and the images digitized before quantification with Multi Gauge software (FujiFilm).
  • Values are percentage and represent activity of enzyme in presence of compound. Values represent duplicate experiments carried out on separate days.
  • EEF-2K Eukaryotic elongation factor-2 kinase.
  • GSK - Glycogen synthase kinase (alpha and beta isoforms).
  • IR - Insulin receptor
  • IRR Insulin receptor-related receptor.
  • PKB/PKC Phosphoralting kinase B/C.
  • SGK Serum- and glucocorticoid- induced kinase.
  • Table 2 Atypical APDs and PI3 kinases.
  • Values (%) represent activity of enzyme in presence of compound relative to controls. Values represent duplicate experiments carried out on separate days.
  • Values (%) represent activity of enzyme in presence of compound relative to controls.

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Abstract

La présente invention concerne un procédé de diagnostic ou de pronostic d'un syndrome métabolique potentiel chez un sujet. La présente invention concerne en outre un procédé de diagnostic ou de pronostic d'un syndrome métabolique potentiel chez un sujet pouvant être induit par des médicaments. La présente invention porte par ailleurs sur l'utilisation d'un agent dans la fabrication d'un médicament destiné à traiter un trouble ou une maladie chez un sujet. La présente invention porte également sur un agent à utiliser dans un procédé destiné à traiter un trouble ou une maladie chez un sujet. En outre, l'invention concerne un procédé de traitement d'un trouble ou d'une maladie chez un sujet, comprenant l'administration d'une quantité thérapeutiquement efficace d'un agent à un sujet. Enfin, la présente invention concerne un procédé d'identification d'un composé anti-psychotique.
PCT/DK2008/050227 2007-09-19 2008-09-18 Diagnostic de la prise de poids potentielle chez un sujet WO2009036768A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013088404A1 (fr) 2011-12-15 2013-06-20 Novartis Ag Utilisation d'inhibiteurs de l'activité ou de la fonction de pi3k
WO2016128348A1 (fr) * 2015-02-13 2016-08-18 F. Hoffmann-La Roche Ag Procédé d'évaluation de la polyarthrite rhumatoïde par mesure des anti-ccp et anti-pik3cd
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives
CN115616113A (zh) * 2022-10-18 2023-01-17 江苏慈星药业有限公司 一种利用hplc测定氯氮平原料药中杂质含量的方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003104239A1 (fr) * 2002-06-05 2003-12-18 Ivax Corporation Compose pour le traitement de troubles du systeme nerveux central (snc)
GB0508471D0 (en) * 2005-04-26 2005-06-01 Celltech R&D Ltd Therapeutic agents
WO2007050318A2 (fr) * 2005-10-24 2007-05-03 Duke University Approches lipidomiques de troubles du systeme nerveux central
US20070154576A1 (en) * 2005-12-09 2007-07-05 Tripp Matthew L Protein kinase modulation by hops and Acacia products
CA2650443A1 (fr) * 2006-05-02 2007-11-15 University Of Southampton Prediction de phenotypes

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013088404A1 (fr) 2011-12-15 2013-06-20 Novartis Ag Utilisation d'inhibiteurs de l'activité ou de la fonction de pi3k
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives
WO2016128348A1 (fr) * 2015-02-13 2016-08-18 F. Hoffmann-La Roche Ag Procédé d'évaluation de la polyarthrite rhumatoïde par mesure des anti-ccp et anti-pik3cd
CN107484423A (zh) * 2015-02-13 2017-12-15 豪夫迈·罗氏有限公司 通过测量抗ccp和抗pik3cd来评估类风湿性关节炎的方法
US10094826B2 (en) 2015-02-13 2018-10-09 Roche Diagnostics Operations, Inc. Method of assessing rheumatoid arthritis by measuring anti-CCP and anti-PIK3CD
CN115616113A (zh) * 2022-10-18 2023-01-17 江苏慈星药业有限公司 一种利用hplc测定氯氮平原料药中杂质含量的方法
CN115616113B (zh) * 2022-10-18 2024-08-06 江苏慈星药业有限公司 一种利用hplc测定氯氮平原料药中杂质含量的方法

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