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WO2010115830A2 - Agent pharmaceutique - Google Patents

Agent pharmaceutique Download PDF

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Publication number
WO2010115830A2
WO2010115830A2 PCT/EP2010/054378 EP2010054378W WO2010115830A2 WO 2010115830 A2 WO2010115830 A2 WO 2010115830A2 EP 2010054378 W EP2010054378 W EP 2010054378W WO 2010115830 A2 WO2010115830 A2 WO 2010115830A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical agent
sugar
glucose
active moiety
pharmaceutically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/054378
Other languages
English (en)
Other versions
WO2010115830A3 (fr
Inventor
Gregory Alan Stoloff
Wilson Romero Caparros-Wanderley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peptcell Ltd
Original Assignee
Peptcell Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peptcell Ltd filed Critical Peptcell Ltd
Publication of WO2010115830A2 publication Critical patent/WO2010115830A2/fr
Publication of WO2010115830A3 publication Critical patent/WO2010115830A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is concerned with pharmaceutical compounds and pharmaceutical compositions for treating obesity and/or diabetes.
  • the invention also concerns methods of manufacture of the pharmaceutical compounds and methods of treatment employing the pharmaceutical compounds and compositions.
  • glycogen may be stored in cells and metabolised into glucose).
  • the primary metabolic response is to restore the haemostatic concentration by breaking down glycogen stored in liver cells into glucose (glycogenosis) which is then exported to blood.
  • glucose glycogenosis
  • hypoglycaemia ensues, which could be fatal.
  • the present invention provides a pharmaceutical agent comprising a pharmaceutically active moiety capable of transforming a sugar (preferably glucose) into a compound that is not metabolised, which pharmaceutically active moiety does not adversely affect blood composition and/or blood characteristics (or does not do so significantly).
  • the pharmaceutically active moiety not adversely affecting blood composition and/or blood characteristics preferably means that the pharmaceutically active moiety is capable of reducing hindering or preventing hypoglycaemia and/or reducing hindering or preventing glycogenosis, and/or is capable of maintaining blood homeostasis (typically blood glucose homeostasis).
  • the mechanism of conversion of glucose (or other sugar) to the compound that is not metabolised is not especially limited, provided that the conversion is safe (i.e. does not adversely affect blood composition or blood characteristics).
  • does not adversely affect means that there is no effect that would require treatment to alleviate that effect, and/or that there is no effect that a medical professional would consider to be problematic.
  • glucose conversion does not lead to hypoglycaemia, and/or it does not cause glycogenosis (preferably it does not cause undue or significant glycogenolysis), and/or it does not lead to adverse changes in blood homeostasis.
  • the mechanism chosen is dependent upon the particular compound into which the sugar (preferably glucose) is transformed.
  • the sugar is transformed into a sugar that is not recognised by insulin, and/or cannot be absorbed by cells from blood, and/or a sugar that cannot be metabolised once in the cells.
  • the sugar is transformed into a modified sugar or sugar derivative that cannot be absorbed from blood by cells either constitutively, or in response to a chemical or hormonal stimulus (e.g. in response to insulin).
  • the skilled person is able to select the compound or sugars to employ based upon known metabolic characteristics of such compounds and sugars.
  • the sugar that cannot be metabolised is lactose, or a derivative of lactose.
  • the pharmaceutically active moiety is not especially limited provided that it is capable of converting a sugar (preferably glucose) into an entity that is not metabolised (in the context of the present invention, metabolised means that the compound is not converted by the body into useful substance(s) and preferably that the compound is a compound that is excreted without taking part in any biological activity).
  • metabolised means that the compound is not converted by the body into useful substance(s) and preferably that the compound is a compound that is excreted without taking part in any biological activity).
  • the pharmaceutically active moiety comprises an enzyme for converting glucose into the compound that is not metabolised.
  • the pharmaceutically active moiety is preferably one or more of the enzymes involved in the conversion of glucose to lactose (see below).
  • glucose-6-phosphate catalysed by hexokinase enzyme.
  • This is in turn transformed into glucose- 1 -phosphate under the action of phosphoglucomutase enzyme.
  • This product is converted into uridine diphosphate glucose (UDP-glucose) by the activity of UDP glucose pyrophosphorylase enzyme.
  • UDP-glucose is converted to UDP-galactose by an epimerase reaction. In the final stages of transformation, UDP-galactose then reacts with glucose- 1 -phosphate to produce lactose.
  • Lactose synthase is a heterodimer (a dimer comprising two different parts): ⁇ -lactalbumin forms the regulatory subunit of the heterodimer and ⁇ -l,4-galactosyltransferase forms the catalytic component. Together, these proteins enable lactose synthase to produce lactose by transferring galactose moieties to glucose.
  • the enzyme is an enzyme selected from hexokinase, phosphoglucomutase, UDP glucose pyrophosphorylase, an epimerase and lactose synthase.
  • the enzyme is lactose synthase.
  • the form of the lactose synthase is not especially limited, provided that it is capable of transforming glucose into lactose.
  • the lactose synthase enzyme may be selected from ⁇ -lactalbumin, ⁇ -l,4-galactosy transferase, and a heterodimer comprising ⁇ -lactalbumin and ⁇ -l,4-galactosyltransferase.
  • the pharmaceutical agent is selected so that glucose conversion occurs as quickly as possible, and involves a small number of synthesis steps. Accordingly, it is preferred that the pharmaceutically active moiety is attached to a moiety that will aid in glucose conversion, such as a carrier moiety.
  • the carrier moiety is preferably UDP-galactose
  • the pharmaceutically active moiety is preferably lactose synthase. This embodiment is especially preferred because the carrier moiety provides the UDP-galactose starting material to which the lactose synthase can attach the glucose.
  • the lactose synthase heterodimer may be replaced by its two separate parts, ⁇ -lactalbumin and ⁇ -l,4-galactosyltransferase. These separate parts may be attached to the same carrier, or may be present as two separate pharmaceutical agents each being present in unattached form, or attached to its own carrier. These separate pharmaceutical agents may be administered simultaneously or sequentially.
  • the carrier moiety is attached to the pharmaceutically active moiety via a linker.
  • the linker is not especially limited provided that it does not interfere with the conversion of the sugar (preferably glucose) to the compound that is not metabolised.
  • the linker comprises a group formed from photoreaction with the pharmaceutically active moiety. More preferably, the linker comprises a group formed from the photoreaction of a diazirine with the pharmaceutically active moiety.
  • linker and the carrier are precursors to the pharmaceutical agent of the invention, and when together may have any of the following structures:
  • the photoreactive linker may be attached via any other of the hydroxyl groups shown in the structure.
  • the final structure of the pharmaceutical agent and compound of the invention will be dependent upon the location of the linker, and whilst preferred structures are provided here and in the following text, all structures formed from attachment of the linker at different OH groups are included, as well as attachments at multiple OH groups.
  • the pharmaceutical agent itself may have the following structure:
  • Carrier moiety wherein the carrier moiety is any carrier moiety described above, the photoreactive linker is a linker capable of attaching to the pharmaceutically active moiety by photoreaction with the pharmaceutically active moiety, the pharmaceutically active moiety is any pharmaceutically active moiety described above, and R 1 and R 2 are independently a substituent as defined below.
  • the substituents are not particularly limited and may comprise any organic group and/or one or more atoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom or a halogen atom (e.g. F, Cl, Br or I).
  • groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table such as a B, Si, N, P, O, or S atom or a halogen atom (e.g. F, Cl, Br or I).
  • the organic group preferably comprises a hydrocarbon group.
  • the hydrocarbon group may comprise a straight chain, a branched chain or a cyclic group. Independently, the hydrocarbon group may comprise an aliphatic or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated or unsaturated group.
  • the hydrocarbon when the hydrocarbon comprises an unsaturated group, it may comprise one or more alkene functionalities and/or one or more alkyne functionalities. When the hydrocarbon comprises a straight or branched chain group, it may comprise one or more primary, secondary and/or tertiary alkyl groups. When the hydrocarbon comprises a cyclic group it may comprise an aromatic ring, an aliphatic ring, a heterocyclic group, and/or fused ring derivatives of these groups.
  • the cyclic group may thus comprise a benzene, naphthalene, anthracene, indene, fluorene, pyridine, quinoline, thiophene, benzothiophene, furan, benzofuran, pyrrole, indole, imidazole, thiazole, and/or an oxazole group, as well as regioisomers of the above groups.
  • the number of carbon atoms in the hydrocarbon group is not especially limited, but preferably the hydrocarbon group comprises from 1-40 C atoms.
  • the hydrocarbon group may thus be a lower hydrocarbon (1-6 C atoms) or a higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms).
  • the number of atoms in the ring of the cyclic group is not especially limited, but preferably the ring of the cyclic group comprises from 3-10 atoms, such as 3, 4, 5, 6 or 7 atoms.
  • the groups comprising heteroatoms described above, as well as any of the other groups defined above, may comprise one or more heteroatoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom or a halogen atom (e.g. F, Cl, Br or I).
  • the substituent may comprise one or more of any of the common functional groups in organic chemistry, such as hydroxy groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulphate groups, sulphonic acid groups, and phosphate groups etc.
  • the substituent may also comprise derivatives of these groups, such as carboxylic acid anhydrydes and carboxylic acid halides.
  • any substituent may comprise a combination of two or more of the substituents and/or functional groups defined above.
  • the diazirine linker preferably has the following substituted or unsubstituted structure:
  • the substituents are not especially limited, provided they do not hinder the conversion of the sugar (preferably glucose) into the compound that is not metabolised.
  • the substituents are each independent of one another and may be any of the substituent groups already described above. They may replace any one or more of the H groups in the above formula.
  • the agent is substituted or unsubstituted and preferably has one of the following structures:
  • the pharmaceutically active moiety is preferably an enzyme selected from hexokinase, phosphoglucomutase, UDP glucose pyrophosphorylase, an epimerase and lactose synthase.
  • the enzyme is lactose synthase.
  • the lactose synthase enzyme may be selected from ⁇ -lactalbumin, ⁇ -l,4-galactosyltransferase, and a heterodimer comprising ⁇ -lactalbumin and ⁇ -l,4-galactosyltransferase, as described above.
  • the substituents are not especially limited, provided they do not hinder the conversion of glucose to lactose.
  • the substituents are each independent of one another and may be any of the substituent groups already described above. They may replace any one or more of the H or OH groups in the above formula.
  • the invention also provides a precursor to the pharmaceutical agent, which precursor comprises a carrier moiety attached to a linker, wherein the carrier moiety comprises substituted or unsubstituted UDP-galactose, and the linker comprises a group capable of photoreaction with a pharmaceutically active moiety.
  • This precursor preferably has one of the following structures:
  • the linker comprises a diazirine group, preferably as defined above.
  • the invention provides a further precursor to a pharmaceutical agent, which precursor comprises a carrier moiety attached to a linker, wherein the linker comprises a diazirine group.
  • This precursor has the following structure: Carrier
  • the carrier moiety comprises substituted or unsubstituted UDP-galactose, preferably as defined above.
  • the pharmaceutically active moiety is preferably any pharmaceutically active moiety as defined above.
  • the precursor can be substituted or unsubstituted.
  • the substituents are not especially limited, provided they do not hinder the conversion of the sugar (preferably glucose) into the compound that is not metabolised.
  • the substituents are each independent of one another and may be any of the substituent groups already described above. They may replace any one or more of the H or OH groups in the precursor.
  • the precursor is substituted or unsubstituted, and has one of the following structures:
  • the substituents are not especially limited, provided they do not hinder the conversion of glucose to lactose.
  • the substituents are each independent of one another and may be any of the substituent groups already described above. They may replace any one or more of the H or OH groups in the above formula.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutical agent as defined above, and optionally one or more further additives.
  • the further additives are not especially limited, and may be selected by the skilled person depending on the mode of administration of the pharmaceutical agent.
  • the agent is for oral, intravenous or subcutaneous administration
  • the further additive may comprise an excipient for oral preparations, an excipient for intravenous preparations, or an excipient for subcutaneous preparations.
  • Administration is preferably in the same manner as insulin is currently delivered, for example using a pen device, such as an injection device that delivers the product subcutaneously in either the stomach, thighs or buttocks or arms.
  • the invention may be given orally in a manner that is sheltered from being broken down by the digestive system and is transported across the intestine by the typical transporter peptides.
  • the invention also provides an agent or composition as described above for use as a medicament.
  • the agent or composition is for use in treating a disease associated with glucose metabolism.
  • the disease associated with glucose metabolism is hyperglycaemia, obesity, type I diabetes and/or type II diabetes.
  • the invention also provides a method of treating a disease associated with glucose metabolism, which method comprises administering to a patient a pharmaceutical agent or a pharmaceutical composition as defined above.
  • the disease associated with glucose metabolism is hyperglycaemia, obesity, type I diabetes or type II diabetes.
  • the diseases involved are diseases in mammals, more preferably diseases in humans.
  • the invention also provides a method of synthesis of the pharmaceutical agent, which method comprises reacting a pharmaceutically active moiety with a precursor using a photoreaction step.
  • the precursor is a precursor as defined above having the photoreactive linker, and the pharmaceutically active moiety is as defined above.
  • DMSO extra dry on molecular sieves, cat 41648, FLUKA
  • UDP-galactose catalogue 670111, Calbiochem
  • DMSO was added to 1 equivalent of UDP-galactose (catalogue 670111, Calbiochem) and left stirring in a closed vessel protected from light at room temperature until UDP-galactose was completely dissolved, this step took 1 hour.
  • 0.5 equivalents of the chlorine form of diazirine were then added.
  • the vessel was closed and the reaction was allowed to proceed for 60 hours with constant stirring while maintained protected from light.
  • the reaction was monitored by TLC in DCM/MeOH (methanol). When the reaction reached completion, DMSO was extracted in vacuo at room temperature and protected from light.
  • the extract of the reaction mixture in step 2 was dissolved in a 400 ⁇ l mixture of 50:50 Millipore purified water:MeOH, and immediately chromato graphed on a Waters Mass Directed purification system using an Atlantis Hilic Silica PREP OBDTM 5 ⁇ M 30x50 mm column, catalogue 186003962 from Waters.
  • reaction and dialysis buffer were prepared, consisting of 0.001 M MnCl 2 , 0.02 M Tris-HCl, 0.2 M NaCl in purified water.
  • ⁇ 1 ,4-galactosyltransferase (MW 44 KDa, catalogue 48279, Sigma- Aldrich) was dissolved in 2 ml of buffer and allowed to dissolve for 15 minutes, 2.4 mg of UDP-galactose- diazirine were dissolved in 1 ml of buffer and added to the mixture. 7 ml of buffer were added and the reaction was allowed to proceed for 15 minutes with stirring, while protected from light.
  • ⁇ -lactalbumin (L5385, Sigma-Aldrich) was dissolved in 1 ml of buffer and added dropwise to the reaction mixture.
  • the reaction vessel was placed under a 360 nm UV lamp (2 x 6 watts) at 5 cm distance, protected from light of other wavelengths and allowed to react for 60 minutes.
  • ⁇ >nd change 1000 ml, 2 hours.
  • 3 rd change 1000 ml, 12 hours.
  • 4 th change 2000 ml, 24 hours. Samples from individual membrane tubes were collected.
  • Conjugate UDP-galactose covalently bonded to Lactose synthase
  • glucose 10 times molar excess of glucose
  • tubes containing either conjugate alone or glucose alone at the same concentrations were incubated for the same length of time at the same temperature.
  • the samples were analysed for glucose in a Bruker UHR-Maxis Q-TOF-MS coupling with a Dionex RS 3000 UHPLC system.
  • a reverse phase C18 column (100 x 2.1 mm, 2.7 ⁇ m) and guard cartridge (trap column) were used with a methanol-water-0.1% formic acid gradient at 0.2 ml/min (0-5 minutes, 100% water, 5-10 minutes, 30% methanol, then isocratic for 5 minutes and return to 100% water in 2 minutes).
  • the mass spectrometer was in full scan positive mode with ESI, calibrated at the beginning of each run.
  • the data shows that whilst glucose could be detected in the glucose only control sample no glucose could be detected in either the conjugate only control sample or the conjugate + glucose sample. Although the absence of glucose in the conjugate sample was expected, the absence of glucose in the conjugate + glucose sample shows that free glucose is consumed by the conjugate.
  • Newly synthesised lactose molecules remain covalently bound to the conjugate and, as protein containing fractions (i.e. large MW) are trapped by the column, are eliminated from the small MW fraction which is then analysed.
  • conjugate Due to the nature of the conjugate, it is possible that more than one molecule of UDP-galactose could be present in the conjugate. That being the case, multiple glucose molecules would be incorporated to the UDP-galactose substrate bound to the protein in order to form lactose.

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agent pharmaceutique comprenant un fragment pharmaceutiquement actif capable de transformer un sucre, de préférence un glucose, en un composé qui n'est pas métabolisé. Ledit fragment pharmaceutiquement actif n'a pas d'effet négatif sur la composition sanguine ni sur les caractéristiques sanguines.
PCT/EP2010/054378 2009-03-31 2010-03-31 Agent pharmaceutique Ceased WO2010115830A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0905555.9 2009-03-31
GBGB0905555.9A GB0905555D0 (en) 2009-03-31 2009-03-31 Pharmaceutical agent

Publications (2)

Publication Number Publication Date
WO2010115830A2 true WO2010115830A2 (fr) 2010-10-14
WO2010115830A3 WO2010115830A3 (fr) 2010-12-23

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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1345964A (zh) * 2000-09-29 2002-04-24 上海博德基因开发有限公司 一种新的多肽——己糖激酶10.01和编码这种多肽的多核苷酸
CN100415899C (zh) * 2001-09-05 2008-09-03 普赖德普罗特奥米克斯公司 Ii型糖尿病蛋白质
JP2006522816A (ja) * 2003-04-11 2006-10-05 ピーアール ファーマシューティカルズ， インコーポレイテッド 部位特異的タンパク質結合体を調製する方法
FR2900342B1 (fr) * 2006-04-27 2010-08-20 Cie Laitiere Europeenne Utilisation de l'alpha-lactalbumine pour la regulation de la glycemie

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RICHARD H. RICHARDSON; KEITH BREW: "Lactose Synthase. An investigation of the interaction site of a-Lactalbumin for Galactosyltransferase by differential kinetic labelling", J BIOL. CHEM., vol. 255, no. 8, 1980, pages 3377 - 3385
RICHARDSON, JBC, vol. 5, 1980, pages 1

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Publication number Publication date
GB0905555D0 (en) 2009-05-13
WO2010115830A3 (fr) 2010-12-23

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