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WO2004037373A2 - Chaperons moleculaires chimiques et leur effet sur l'activite cellulaire de $g(b)-glucosidase - Google Patents

Chaperons moleculaires chimiques et leur effet sur l'activite cellulaire de $g(b)-glucosidase Download PDF

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Publication number
WO2004037373A2
WO2004037373A2 PCT/US2003/033670 US0333670W WO2004037373A2 WO 2004037373 A2 WO2004037373 A2 WO 2004037373A2 US 0333670 W US0333670 W US 0333670W WO 2004037373 A2 WO2004037373 A2 WO 2004037373A2
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WIPO (PCT)
Prior art keywords
group
substituted
formula
compound
glucosidase
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Ceased
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PCT/US2003/033670
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English (en)
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WO2004037373A3 (fr
Inventor
Jeffrey W. Kelly
Anu R. Sawkar
Ernest Beutler
Chi-Heuy Wong
William E. Balch
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Scripps Research Institute
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Scripps Research Institute
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Priority to AU2003284886A priority Critical patent/AU2003284886A1/en
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Publication of WO2004037373A3 publication Critical patent/WO2004037373A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • Enzyme replacement can be accomplished by protein infusions. Enzyme replacement for the most prevalent lysosomal storage disease, Gaucher disease, costs between $100,000 and $750,000 per year and is not very effective for the treatment of CNS involvement. While the enzyme has been modified to take advantage of mannose receptor-mediated endocytosis by macrophages, studies in rats suggest that less than 7% of the enzyme is taken up into liver macrophages (5), and the uptake in human bone marrow macrophages is so low that it is difficult to detect (6). Transplantation of hematopoietic stem cells can also reverse the disease, but thus far, attempts at gene transfer have been unsuccessful.
  • Gaucher disease is the most prevalent lysosomal storage disorder with an estimated incidence of 1 in 40,000 to 60,000 in the general population (13) and 1 :800 among the Ashkenazi Jewish population (14).
  • Five mutant alleles of ⁇ - glucosidase ( ⁇ -Glu, glucocerebrosidase) account for the majority of reported cases (15). Accumulation of the substrate (glucosylceramide) leads to hepatomegaly, splenomegaly, bone crisis, anemia, and central nervous system (C ⁇ S) involvement.
  • the activity of Gaucher disease associated beta-glucosidase activity can be increased by exposing the glucosidase to an effective activating amount of a chemical chaperone specific for the glucosidase.
  • disease associated glucosidase activity can be increased through the use of a sugar-mimic heterocycle.
  • sugar-mimic heterocycles include those having five or six membered rings wherein one or two of the members are heteroatoms. Preferred heteroatoms are oxygen (O) and nitrogen (N).
  • NN-DNJ has been shown to increase the activity of both N370S and wt ⁇ -Glu in fibroblasts, presumably through protein stabilization, as demonstrated in vitro. However, it does not enhance the intracellular activity of the L444P variant.
  • Clinical data indicate that a small increase in enzyme activity may be effective in treating disease. Although patients receiving Cerezyme infusions experience reduced hepatosplenomegaly, improved blood counts, and amelioration of bone crises, the increase of enzyme activity in bone marrow due to treatment can be quite small. After infusion of either 1.15 U/kg or 60 U/kg of enzyme into five patients, a 1.7-9.6-fold increase of ⁇ -Glu activity was observed (6).
  • 1 -deoxynojirimycin (D ⁇ J) can be prepared from 2,3,4,6-tetra-O-benzyl- ⁇ -glucopyranose, see reference 23.
  • 2,5- Anhydro-imino-D-glucitol can be prepared from 5-keto-D-fructose according to Reitz's method, see references 24 and 25.
  • ⁇ -alkyl compounds can prepared by reductive amination of the alkyl aldehyde with the corresponding nitrogen heterocycle such as 2,5-anhydro-imino-D-glucitol, morpholine, 1- (hydroxyethyl)piperazine, isofagamine, or trans-3-hydroxy-L-proline.
  • adamantyl, cyclohexyl or bicycloheptyl moieties can be added by either of two methods. The first involves addition of an omega-haloalkanoic ester to the heterocycle nitrogen through an amine alkylation reaction. The ester is then deprotected to form the carboxylic acid and the acid group is condensed with the amine or hydroxy-adamantane, cyclohexane or bicycloheptane.
  • the carrier is usually hydrophobic and commonly organic, e.g., an oil or fat of vegetable, animal, mineral or synthetic origin or derivation.
  • the carrier includes at least one chemical moiety of the kind that typifies "fatty" compounds, e.g., fatty acids, alcohols, esters, etc., i.e., a hydrocarbon chain, an ester linkage, or both.
  • "Fatty” acids in this context include acetic, propionic and butyric acids through straight- or branched-chain organic acids containing up to 30 or more carbon atoms.
  • the carrier is immiscible in water and/or soluble in the substances commonly known as fat solvents.
  • a disintegrator is a substance, or a mixture of substances, added to a tablet to facilitate its breakup or disintegration after administration.
  • the active ingredient must be released from the tablet matrix as efficiently as possible to allow for its rapid dissolution.
  • Materials serving as disintegrates have been chemically classified as starches, clays, celluloses, aligns, or gums.
  • Example 1 Alkylated deoxynoiirimycin analogues increase lysosomal ⁇ -glucosidase activity.
  • Example 4 Probing the requirements for N370S ⁇ -glucosidase chaperoning with simple amphipathic molecules and alkylated nitrogen heterocycles.
  • ⁇ -Glu activity especially in the case of the N370S mutant, is stimulated by detergents, bile salts, phosphatidylserine, and the activator protein Saposin C (19).
  • the mechanisms by which these molecules enhance enzyme activity are not known, hence it was decided to test different types of amphipathic molecules.
  • a series of charged and neutral amphipathic molecules were evaluated over a concentration range of 5-200 ⁇ M. We compared both wt and N370S cell lines because both proteins could potentially be stabilized by these molecules.
  • the iminocyclitol 2 a known transition state mimetic, only slightly increased ⁇ -Glu activity, whereas related 5-membered ring N-heterocycles 5 and 6 were inactive (34).
  • the morpholine and piperazine based molecules 3 and 4 showed some activity despite their inability to form numerous hydrogen bonds in the active site thought to be important for the binding of 1 to ⁇ -Glu.
  • the latter compounds may be able to form an ion pair with the putative active site carboxylate because of their structures.
  • the piperazine and morpholine compounds had measurable IC 50 values (high ⁇ M range) while 5 and 6 had IC 50 values in the mM range. This may explain why the former compounds are active and the latter are not.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un processus permettant d'accroître l'activité de β-glucosidase associée à la maladie de Gaucher. Ce processus consiste à exposer la glucosidase à un chaperon moléculaire chimique qui présente un taux élevé de l'activité des chaperons moléculaires par rapport à l'activité inhibitrice de la glucosidase. Des chaperons exemplaires et préférés constituent un composé de déoxynojirimycine volumineux au niveau stérique et un composé 2,5-didéoxy-2,5-imino-D-mannitol volumineux au niveau stérique. Cette invention a aussi trait à un processus de stabilisation de la β-glucosidase.
PCT/US2003/033670 2002-10-21 2003-10-21 Chaperons moleculaires chimiques et leur effet sur l'activite cellulaire de $g(b)-glucosidase Ceased WO2004037373A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003284886A AU2003284886A1 (en) 2002-10-21 2003-10-21 CHEMICAL CHAPERONES AND THEIR EFFECT UPON THE CELLULAR ACTIVITY OF Beta-GLUCOSIDASE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42047302P 2002-10-21 2002-10-21
US60/420,473 2002-10-21

Publications (2)

Publication Number Publication Date
WO2004037373A2 true WO2004037373A2 (fr) 2004-05-06
WO2004037373A3 WO2004037373A3 (fr) 2004-07-15

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WO (1) WO2004037373A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009066069A1 (fr) * 2007-11-21 2009-05-28 Summit Corporation Plc Traitement de troubles de repliement de protéine
US7741340B2 (en) 2003-11-12 2010-06-22 Amicus Therapeutics, Inc. Hydroxy piperidine derivatives to treat gaucher disease
WO2012001641A1 (fr) * 2010-06-30 2012-01-05 Actelion Pharmaceuticals Ltd Compositions pharmaceutiques stables
WO2014102417A1 (fr) * 2012-12-26 2014-07-03 Consejo Superior De Investigaciones Científicas (Csic) Utilisation de dérivés bicycliques de 1-désoxigalactonojirimicine dans la préparation d'un médicament pour el traitement de maladies en relation avec les β-enzymes galactosidases lisosomiques mutantes humaines
EP2932982A1 (fr) 2005-05-17 2015-10-21 Amicus Therapeutics, Inc. Procédé pour le traitement de la maladie de Pompe au moyen de 1-désoxynojirimycine et de ses dérivés
US9353117B2 (en) 2010-12-08 2016-05-31 The United States Of America As Represented By The Secretary, Dept. Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
EP3088389A1 (fr) * 2015-04-28 2016-11-02 Dorphan S.A. Dérivés de 4-epi-isofagomine
US9597377B2 (en) 2003-01-31 2017-03-21 Mount Sinai School Of Medicine Of New York University Stable formulations of purified proteins
US9956236B2 (en) 2011-02-07 2018-05-01 Cornell University Methods for increasing immune responses using agents that directly bind to and activate IRE-1
US9957506B2 (en) 2013-09-25 2018-05-01 Cornell University Compounds for inducing anti-tumor immunity and methods thereof
WO2019211205A1 (fr) 2018-04-30 2019-11-07 Dorphan S.A. Compositions pharmaceutiques destinées à être utilisées dans le traitement de maladies lysosomales
WO2020046132A1 (fr) 2018-08-31 2020-03-05 Leiden University Chaperons pharmacologiques pour une thérapie par traitement enzymatique
NL2021840B1 (en) 2018-10-19 2020-05-13 Univ Leiden Pharmacological Chaperones For Enzyme Treatment Therapy
US10655130B2 (en) 2012-03-09 2020-05-19 Cornell University Modulation of breast cancer growth by modulation of XBP1 activity

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5231185A (en) * 1985-11-19 1993-07-27 Cornell Research Foundation, Inc. Monosaccharide analog-based glycosidase inhibitors
US6274597B1 (en) * 1998-06-01 2001-08-14 Mount Sinai School Of Medicine Of New York University Method of enhancing lysosomal α-Galactosidase A
EP1196190B1 (fr) * 1999-07-26 2003-03-19 G.D. SEARLE & CO. Utilisation de derives n-alkyle de deoxynojirimycine a chaine longue et d'enzyme glucocerebro-sidase pour fabriquer un medicament permettant de traiter des maladies provoquees par le stockage de glycolipides

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9597377B2 (en) 2003-01-31 2017-03-21 Mount Sinai School Of Medicine Of New York University Stable formulations of purified proteins
US7741340B2 (en) 2003-11-12 2010-06-22 Amicus Therapeutics, Inc. Hydroxy piperidine derivatives to treat gaucher disease
EP3441090A1 (fr) 2005-05-17 2019-02-13 Amicus Therapeutics, Inc. Procédé pour le traitement de la maladie de pompe au moyen de 1-désoxynojirimycine et de ses dérivés
EP2932982A1 (fr) 2005-05-17 2015-10-21 Amicus Therapeutics, Inc. Procédé pour le traitement de la maladie de Pompe au moyen de 1-désoxynojirimycine et de ses dérivés
EP3782655A1 (fr) 2005-05-17 2021-02-24 Amicus Therapeutics, Inc. Procédé pour le traitement de la maladie de pompe au moyen de 1-désoxynojirimycine et de ses dérivés
WO2009066069A1 (fr) * 2007-11-21 2009-05-28 Summit Corporation Plc Traitement de troubles de repliement de protéine
WO2012001641A1 (fr) * 2010-06-30 2012-01-05 Actelion Pharmaceuticals Ltd Compositions pharmaceutiques stables
US9353117B2 (en) 2010-12-08 2016-05-31 The United States Of America As Represented By The Secretary, Dept. Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
US10925874B2 (en) 2010-12-08 2021-02-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
US9974789B2 (en) 2010-12-08 2018-05-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
US9956236B2 (en) 2011-02-07 2018-05-01 Cornell University Methods for increasing immune responses using agents that directly bind to and activate IRE-1
US10655130B2 (en) 2012-03-09 2020-05-19 Cornell University Modulation of breast cancer growth by modulation of XBP1 activity
WO2014102417A1 (fr) * 2012-12-26 2014-07-03 Consejo Superior De Investigaciones Científicas (Csic) Utilisation de dérivés bicycliques de 1-désoxigalactonojirimicine dans la préparation d'un médicament pour el traitement de maladies en relation avec les β-enzymes galactosidases lisosomiques mutantes humaines
US9957506B2 (en) 2013-09-25 2018-05-01 Cornell University Compounds for inducing anti-tumor immunity and methods thereof
US10450566B2 (en) 2013-09-25 2019-10-22 Cornell University Compounds for inducing anti-tumor immunity and methods thereof
US10421965B2 (en) 2013-09-25 2019-09-24 Cornell University Compounds for inducing anti-tumor immunity and methods thereof
WO2016174131A1 (fr) * 2015-04-28 2016-11-03 Dorphan S.A. Dérivés d'énantionère de 4-épi-isofagomine pour le traitement des maladies lysosomales
EP3088389A1 (fr) * 2015-04-28 2016-11-02 Dorphan S.A. Dérivés de 4-epi-isofagomine
WO2019211205A1 (fr) 2018-04-30 2019-11-07 Dorphan S.A. Compositions pharmaceutiques destinées à être utilisées dans le traitement de maladies lysosomales
WO2020046132A1 (fr) 2018-08-31 2020-03-05 Leiden University Chaperons pharmacologiques pour une thérapie par traitement enzymatique
NL2021840B1 (en) 2018-10-19 2020-05-13 Univ Leiden Pharmacological Chaperones For Enzyme Treatment Therapy

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Publication number Publication date
WO2004037373A3 (fr) 2004-07-15
AU2003284886A1 (en) 2004-05-13
AU2003284886A8 (en) 2004-05-13

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