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WO2001097816A1 - Utilisation d'activateurs d'amp kinase pour traiter le diabete de type 2 et la resistance a l'insuline - Google Patents

Utilisation d'activateurs d'amp kinase pour traiter le diabete de type 2 et la resistance a l'insuline Download PDF

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WO2001097816A1
WO2001097816A1 PCT/US2001/019283 US0119283W WO0197816A1 WO 2001097816 A1 WO2001097816 A1 WO 2001097816A1 US 0119283 W US0119283 W US 0119283W WO 0197816 A1 WO0197816 A1 WO 0197816A1
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protein kinase
activated protein
glut4
kinase activator
muscle
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William Winder
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Brigham Young University
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • the present invention relates to the methods of treatment of type 2 diabetes and insulin resistance. More specifically, the invention relates to methods of treatment of type 2 diabetes and insulin resistance through artificial activation of AMP kinase.
  • Type 2 diabetes is characterized by relative insensitivity to the actions of insulin on glucose uptake.
  • American Diabetes Association Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes 1998; 21:S5-S19, 1998; Ferrannini, ⁇ EndocrRev 19:477-490 (1997); Gerich, JE Endocr Rev 19:491-503 (1997).
  • increased insulin secretion can compensate for the insensitivity, but in later stages, insulin deficiency can occur resulting in marked hyperglycemia.
  • Patients with Type 2 diabetes also have dyslipidemia and increased hepatic glucose production.
  • the skeletal muscle sarcolemma and its transverse-tubule (T-tubule) extensions into the muscle fiber interior allow glucose entry into the muscle sarcoplasm via glucose transporters.
  • Each of these transporters consists of a protein that forms a selective hydrophilic passageway through the phospholipid bilayer of the sarcolemma (plasma membrane of muscle), which is a barrier to entrance of water soluble molecules to the interior of the muscle fiber.
  • glucose transporters There are several kinds of glucose transporters, only one of which is controlled by insulin.
  • GLUT4 the insulin sensitive glucose transporter, is present in the muscle fiber in two locations: inserted into the membranes of the sarcolemma and T-tubules, and inserted into the membrane of micro vesicles in the sarcoplasm. In the absence of insulin stimulation, the majority of these transporters are located in the microvesicles in the sarcoplasm.
  • insulin receptor substrate-1 IRS-1
  • the phosphorylated tyrosine residues of IRS-1 (a protein) then serve as docking/activation sites to activate other proteins in the signaling pathway, including phosphatidyl-inositol-3-kinase (PI3K). Activation of PI3K then triggers by undefined mechanisms, the translocation of GLUT4 from the microvesicle fraction to the membrane fraction (sarcolemma and T-tubules). Pessin, JE et al. JBiol Chem 274:2593-2596 (1999). The increased numbers of GLUT4 in the surface membranes provide additional passageways for entrance of glucose into the interior of the muscle fiber.
  • PI3K phosphatidyl-inositol-3-kinase
  • Insulin-induced uptake of 3MG and translocation of GLUT4 to the surface membrane in the epitrochlearis muscle from the fatty Zucker rat is markedly attenuated compared to normal rats.
  • the epitrochlearis from the endurance trained rats showed an approximate doubling of GLUT4.
  • Glucose transport was normalized in epitrochlearis muscles of fatty Zucker rats that were trained on the treadmill for two weeks.
  • the ZDF rats were not deficient in GLUT4, but insulin fails to trigger sufficient translocation/activation to allow normal glucose transport.
  • the mechanism of how training induced increased expression of GLUT4 in ZDF muscle compensates for the deficiency in insulin-stimulated glucose transport is not well-defined, these studies provide evidence that the contraction-induced pathway may indeed be useful for treatment of type 2 diabetes.
  • the invention relates to a method of treating type 2 diabetes in a mammal.
  • the method includes the step of administering a therapeutically effective amount of an AMP- activated protein kinase activator to the mammal.
  • the mammal may be for example, a human, a rat, a mouse, and the like.
  • the AMP-activated protein kinase activator can be subcutaneously injected into the mammal or administered in any other manner that provides for uptake of the AMP-activated protein kinase activator into the cells of the mammal.
  • the activation of the AMP-activated protein kinase activator can produce the benefits of exercise training including the translocation of GLUT4 in the muscle cells of the mammal.
  • the invention also relates to a method of treating insulin resistance in a mammal suffering from obesity, type 2 diabetes, or muscle paralysis.
  • a therapeutically effective amount of an AMP-activated protein kinase activator is given to the mammal.
  • AMP-activated protein kinase can be activated allosterically by increases in the concentration of AMP or by a compound that is analogous to AMP.
  • an AMP analog is administered to a subject so that the AMP analog is taken into the muscle cells of the subject. This may require modification of the analog so that it may be transported into the cell.
  • the AMP analog may be adenosine-5'- thiomonophosphate, adenosine 5'-phosphoramidate, formycin A 5'-monophosphate, or ZMP Because these AMP analogs are not readily transported into a cell the analog may be administered intracellularly.
  • 5-aminoimidazole-4-carboxamide ribonucleoside is an AMP analog that is phosphorylated in muscle cells to become ZMP. This allows the 5-aminoimidazole-4- carboxamide to enter the cells and then be converted to ZMP to mimic the effect of AMP in the cell.
  • 5-aminoimidazole-4-carboxamide ribonucleoside can be administered at a dose from about 0.5 to at least about 1.0 mg/g body weight.
  • the AMP-activated protein kinase activator is administered acutely in a single dose. Such acute administration will result in the activation of AMP kinase for a relatively short period of time. Because the majority of the benefit of exercise in patients suffering from type 2 diabetes or insulin resistance is seen after an extended period of exercise training, the AMP-activated protein kinase activator can be administered chronically. Chronic administration of the AMP anolog refers to the administration of one or more doses daily of an AMP analog for two or more days. For example, one or more daily doses of an AMP analog for a period of weeks has been shown to provide an additional benefit to the subject. To better mimic the effect of exercise training the AMP-activated protein kinase activator can be administered intermittently for a period of time.
  • Figure 1 is a set of bar graphs illustrating AMPK activity in the muscles of rats following an injection with AICAR or a saline control.
  • Figure 2 is a graph showing citrate dependence of acetyl-CoA carboxylase in the muscles of rats injected with AICAR or a saline control.
  • Figure 3 illustrates the Western blot analysis of GLUT4 protein in muscles of rats injected with AICAR or a saline control for 5 days.
  • Figure 4 is a set of bar graphs illustrating relative GLUT4 levels in the muscles of rats treated with AICAR or a saline control for 5 days.
  • Figure 5 is a set of bar graphs illustrating the effect on hexokinase activity in muscles of rats injected with AICAR or a saline control for 5 days.
  • the invention relates to a method of treating type 2 diabetes in a mammal.
  • the method of the present invention may also be used to treat insulin resistance in a mammal suffering from obesisty, type 2 diabetes, or muscle paralysis.
  • the method includes the step of administering a therapeutically effective amount of an AMP-activated protein kinase activator to the mammal.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • therapeutically effective amount is intended to mean an amount of a compound sufficient to produce the desired pharmacological effect. It is understood that the therapeutically effective amount to be used in the treatment of type 2 diabetes or insulin resistance must be subjectively determined according to the type of mammal and the desired effect.
  • Nariables involved include the size of the patient, the type of AMPK activator, the state of the disease, age of the patient, and response pattern of the patient.
  • the novel methods of the invention for treating, preventing or alleviating the conditions described herein comprise administering to mammals in need thereof, including humans, an effective amount of one or more compounds of this invention or a non-toxic, pharmaceutically acceptable addition salt thereof.
  • the compounds may be administered subcutaneously, orally, rectally, parenterally, or topically to the skin and mucosa.
  • many of the known AMP analogs are phosphorylated, it is difficult to get an effective amount of the analog inside a cell by injection or topical methods. Thus, it may be necessary to administer the analog directly into the muscle of the mammal by for example methods of in vivo electroporation.
  • the mammal may be for example, a human, a rat, a mouse, and the like.
  • the AMP-activated protein kinase activator can be subcutaneously injected into the mammal or administered in any other manner that provides for uptake of the AMP-activated protein kinase activator into the cells of the mammal.
  • the activation of the AMP- activated protein kinase activator can produce the benefits of exercise training including the loss of body fat.
  • AMP-activated protein kinase can be activated allosterically by increases in the concentration of AMP or by a compound that is analogous to AMP.
  • an AMP analog such as adenosine-5'-thiomonophosphate, adenosine 5'- phosphoramidate, formycin A 5'-monophosphate, or ZMP is administered to a subject so that the AMP analog is taken into the cells of the subject. This may require modification of the analog so that it maybe transported into the cell. Because these AMP analogs are not readily transported into a cell the analog may be administered intracellularly.
  • 5-aminoimidazole-4-carboxamide ribonucleoside is an AMP analog that is phosphorylated in muscle cells to become ZMP. This allows the 5-aminoimidazole-4- carboxamide to enter the cells and then be converted to ZMP to mimic the effect of AMP in the cell.
  • 5-aminoimidazole-4-carboxamide ribonucleoside can be administered at a dose from about 0.5 to at least about 1.0 mg/g body weight. It has been shown that an effective dose in a rat is about 1.0 mg/g body weight. However, when determining the dose the treatment of a human, the dose may be higher or lower.
  • the AMP-activated protein kinase activator is administered acutely in a single dose. This provides the acute activation of AMPK and provides for a short-lived effect similar to a single bout of exercise.
  • the AMP- activated protein kinase activator can be administered chronically over a period days or weeks to provide an additional benefit to the subject. Providing a dose for a chronic period of about 28 days has been shown to give significant benefits over a single acute activation of AMPK.
  • the AMPK activator can also be administered intermittently over a period of time to better mimic the effect of exercise training.
  • Such intermittent activation can consist of activating AMPK for a period of at least one day, followed by a period of non-activation for at least one day, followed by an additional period of activation of at least one day.
  • the period of activation followed by non-activation can be repeated as needed to obtain the desired results. For example an increased effectiveness was observed when rats were intermittently injected with AICAR as follows: injection for 3 days, followed by 2 days without injection, followed by 5 days of injection, followed by two days without injection, followed by 3 days with injection.
  • Etgen, et al demonstrated that two weeks of exercise, 1 hour per day, would increase total GLUT4 and compensate for this defect in the fatty Zucker rat, an animal model of type 2 diabetes.
  • chemical stimulation of AMPK can be used to increase GLUT4 and to treat insulin resistance and type 2 diabetes.
  • GLUT4 m-RNA is increased in muscle in response to endurance exercise training.
  • the GLUT4 gene has what has been termed an exercise response element residing between 442 and 1000 base pairs upstream from the transcription start site.
  • Ezaki O. Biochem. Biophys. Res. Comm. 241:1-6 (1997); Tsunoda, N. et al. Biochem. Biophys. Res. Comm. 239:503-509 (1997).
  • Nuclear run-on analyses have clearly demonstrated an increase in muscle GLUT4 mRNA synthesis with training. Neufer, P.D. & G.L. Dohm. Am. J. Physiol. 265:C1597-C1603 (1993).
  • GLUT4 and hexokinase gene expression increases in response to AMPK activation. Transcription factors binding to that region of the gene can be screened to see if they have target sites for phosphorylation by AMPK. Previous studies provide evidence of regulation of transcription of hepatocyte genes by AMPK. Treatment of isolated hepatocytes with AICAR has been shown to decrease pyruvate kinase and fatty acid synthetase gene expression.
  • AMPK activation will increase glucose uptake.
  • AMPK is shown herein to be chemically activated by AICAR, thus mimicking the effect of muscle contraction.
  • AICAR also induces the translocation of the GLUT4 transporter to the membrane surface of the muscle, thus allowing an increase in glucose uptake. See Kurth-Kraczek et al. Diabetes 48:1667-1671 (1999).
  • One of the defects of type 2 diabetes is that the muscle becomes less sensitive to insulin. This defect appears to be a deficiency in the amount of GLUT4 translocated to the cell surface in response to insulin. Treatment with AICAR results in an increase of the total GLUT4 and hexokinase in the muscle. This is also a benefit to patients with type 2 diabetes.
  • AICA-riboside is the only adenosine analog that has been found useful in activating AMPK in vivo and which has been utilized to show effects of chronic activation of this kinase.
  • exercise has an acute insulin-like effect
  • actions of AMP-activated protein kinase (3) AMPK can be artificially activated
  • AMPK mediates the effect of muscle exposure to exercise.
  • This kinase is activated by the increase in 5 '-AMP and the decline in creatine phosphate that occur during muscle contraction. Phosphorylated AMPK then presumably phosphorylates undefined target proteins which in turn increase glucose uptake and transcription of the GLUT4 gene.
  • AMP-activated protein kinase was discovered at approximately the same time as cAMP-dependent protein kinase, but only recently have important regulatory functions relating to diabetes been elucidated. Winder, WW & Hardie, DG Am JPhysiol 277:E1-E10 (1999). It consists of three subunits ( ⁇ , ⁇ , and ⁇ ) and for each subunit there are at least two different isoforms. Hardie, DG & Carling, D Eur J Biochem 246:259-273 (1997); Hardie, DG et al. Ann Rev Biochem 67:821-855 (1998). This kinase is activated by both phosphorylation and allosteric mechanisms.
  • AMPKK upstream kinase
  • CP creatine phosphate
  • AMPK plays the role of phosphorylating and inactivating acetyl-CoA carboxylase (ACC) and 3-hydroxy-3- methylglutaryl-CoA reductase (HMGR), the rate limiting enzymes of fatty acid and cholesterol biosynthesis.
  • AMPK is activated in skeletal muscle of rats during treadmill running and in response to electrical stimulation.
  • ATP is used as a source of energy, generating ADP and inorganic phosphate.
  • the ADP can be phosphorylated to form ATP in the glycolytic pathway in the sarcoplasm or by oxidative phosphorylation in the mitochondria.
  • ⁇ on-oxidative, rapidly acting mechanisms also include the action of myokinase, which makes one ATP and one 5'-
  • Malonyl-CoA is a potent inhibitor of carnitine palmitoyl-transferase 1 (CPT 1), the rate limiting step in transfer of long-chain fatty acyl-CoA into the mitochondria where oxidation can occur.
  • CPT 1 carnitine palmitoyl-transferase 1
  • AMPK was found to be activated in the exercising muscle concurrently with inactivation of ACC and a drop in malonyl-CoA. Winder, WW & Hardie, DG Am JPhysiol 270:E299-E304 (1996).
  • the decline in malonyl-CoA was postulated to be important in allowing an increase in fatty acid oxidation as exercise continued.
  • 6.3 AMPK Can Be Artificially Activated
  • AICAR 5-aminoimidazole-4-carboxamide-riboside
  • AICAR is taken up by cells and phosphorylated to form the corresponding monophosphorylated nucleotide (ZMP), an analog of 5'- AMP.
  • ZMP monophosphorylated nucleotide
  • AICAR injection (0.25 mg/g body weight) acutely decreases blood glucose for 4-6 hours in normal mice (C57/BJ6), insulin deficient diabetic mice (C57/BJ6-STZ), and in insulin resistant diabetic mice (KKA 3 ). Nakano, M et al. Diabetes 49(suppl 1):A12 (2000).
  • AMPK activation is an important intermediate step, coupling muscle contraction with an increase in GLUT4 translocation and glucose uptake by the muscle.
  • Example 1 Acute Injection of AICAR All procedures were approved by the Institutional Animal Care and Use
  • AICAR 1 mg/g body weight
  • rats were anesthetized by intravenous injection of pentobarbital (4.8 mg/100 g body weight).
  • pentobarbital 4.8 mg/100 g body weight
  • the epitrochlearis and gastrocnemius/plantaris muscles were quickly removed and rapidly frozen with stainless steel clamps at liquid nitrogen temperature.
  • Blood was collected via the abdominal aorta and a perchloric acid extract was prepared (0.5 ml blood to 2.0 ml 10%) HClO 4 ), neutralized and utilized for analysis of glucose and lactate.
  • Muscles from rats killed 1 hour following injection of AICAR or saline were analyzed for AMPK, citrate-dependence of acetyl-CoA carboxylase, malonyl-CoA, glycogen, ZMP, ZTP, ATP, and ADP. Hassid, W.Z. & S. Abraham Methods Enzymol. 3:35-36 (1957); McGarry, J.D. et al. J Biol. Chem. 253:8291-3293 (1978). Blood glucose and lactate were measured by enzymatic techniques. Bergmeyer, H.U., et al. D- Glucose determination with hexokinase and glucose-6-phosphate dehydrogenase. In:
  • the levels of tissues and blood metabolites of rats sacrificed 60 minutes following an injection are shown in Table 1. ATP and ADP were not influenced by the injection with AICAR. ZTP increased from non-detectable levels to 1.2 ⁇ mol/g. Rats injected with AICAR were found to have significantly increased blood lactate (p ⁇ 0.001) and decreased blood glucose (p ⁇ 0.01) compared to controls. Muscle glycogen and liver glycogen were not acutely influenced 60 minutes following a single injection of AICAR.
  • the maximal velocity of the reaction (Vmax) as a fi-mction of citrate concentration was reduced from 60.1 ⁇ 1.3 to 32.4 ⁇ 1.3 mnol/g/min (p ⁇ 0.001).
  • the citrate activation constant (Ka) was increased from 3.1 ⁇ 0.1 to 13.0 ⁇ 0.3 mM (p ⁇ 0.001). Because of the limited amount of tissue, the entire citrate activation curve could not be determined for epitrochlearis muscle, but the activity of ACC at a physiological concentration of citrate (0.2 mM) was reduced from 0.50 ⁇ 0.10 nmol/g/min to 0.10 ⁇ 0.03 nmol/g/min. Gastrocnemius/plantaris malonyl-CoA was likewise significantly (p ⁇ 0.001) lower in the AICAR injected rats compared to controls 1 hour following the injection as shown in Table 1.
  • AMPK is activated in epitrochlearis and gastrocnemius/plantaris of rats injected with AICAR. Additional evidence of activation of AMPK is provided by the fact that the kinetic properties of ACC change similarly to what is seen when purified ACC is phosphorylated in vitro. Winder, W.W. & D.G. Hardie, Am. J Physiol. 270:E299-E304 (1996). ACC is a downstream target protein for AMPK.
  • the decrease in blood glucose in response to a single injection of AICAR is consistent with either an increase in glucose uptake into peripheral tissues and/or a decrease in glucose production by the liver.
  • the increase in glucose uptake stimulated by AICAR results in increased rates of lactate production in the resting muscle. Kurth- Kraczek, E.J. et al. Diabetes 48 (1999); Merrill, G.F. et al. Am. J. Physiol. 273(36):E1107-E1112 (1997).
  • the increase in concentration of blood lactate in the AICAR injected rats is consistent with the idea that glucose uptake is enhanced resulting in increased glycolytic flux. Liver glycogenolysis or glycogen synthesis did not appear to be influenced 60 minutes following an AICAR injection.
  • Hepatic gluconeogenesis may be inhibited at the fructose-l,6-bisphosphatase reaction.
  • a reduction in utilization of lactate for glucose production by the liver may also have contributed to the decrease in blood glucose and increase in blood lactate.
  • a homogenate (1 :9 dilution) was prepared in HEPES buffer ( 25 mM HEPES, 1 mM EDTA, 1 mM benzamidine, 1 mM 4-(2-aminoethyl)-benzene + sulfonyl fluoride (AEBSF), 1 ⁇ M leupeptin, 1 ⁇ M pepstatin, 1 ⁇ M aprotinin, pH 7.5). Proteins of these homogenates were separated by SDS-PAGE using 10% resolving gels (Tris-HCl ready gels, BIO-RAD, Hercules, CA). Proteins were transferred from the gel to a nitrocellulose membrane at 100 volts for 60 min.
  • HEPES buffer 25 mM HEPES, 1 mM EDTA, 1 mM benzamidine, 1 mM 4-(2-aminoethyl)-benzene + sulfonyl fluoride (AEBSF), 1 ⁇ M leupept
  • the membranes were blocked with 3% BSA in 139 mM NaCl, 2.7 mM KH 2 PO 4 , 9.9 mM Na ⁇ O ⁇ and 0.05% Tween-20 (PBST) and 1% sodium azide. After two 5 minutes washes in 139 mM NaCl, 2.7 mM KH 2 PO 4 , 9.9 mM Na 2 HPO 4 (PBS) , membranes were incubated with GLUT4 polyclonal antibody RalRGT, Biogenesis, Sandown, NH) for 1 hour at room temperature.
  • PBST Tween-20
  • Total intensity of GLUT4 spots on the developed hyperfilm was expressed as a fraction of intensity shown by a GLUT4 standard run on the same gel.
  • the GLUT4 standard was a plasma membrane fraction prepared as described previously. Kurth-Kraczek, E. J. et al. Diabetes 48 (1999).
  • Hexokinase activity was determined spectrophotometrically at 30 C on 700 X g supernatants of the same homogenate as was used for GLUT4 measurement. Uyeda, K. & E. Racker, JBiol Chem 240:4682-4688 (1965). Results are expressed as means ⁇ SEM. Statistically significant differences between control and AICAR treated rats were determined using Student's t test.
  • Figures 3 and 4 show marked increases in GLUT4 in both epitrochlearis and in gastrocnemius/plantaris in response to injection of rats with AICAR for five days.
  • Western blots of total GLUT4 protein in epitrochlearis and gastrocnemius/plantaris muscles from two rats injected with AICAR (1 mg/g body weight) and from two rats injected with saline for 5 days are shown in Figure 3. While the relative GLUT4 levels in epitrochlearis of rats treated for 5 days with AICAR (1 mg/g/d) are shown in Figure 4.
  • Relative total intensity of GLUT4 from muscles from AICAR and saline-injected rats is expressed as a fraction of intensity of standard GLUT4 spots run on all gels.
  • larger rats weighing 350-450 grams
  • responded to AICAR injections 0.5 mg/g body weight
  • n 5/grou ⁇
  • the increased GLUT4 in the muscle may allow increased glucose uptake (after the acute effects of AICAR are gone) and the accumulation of more than double the amount of glycogen seen in the saline- injected controls.

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Abstract

L'invention concerne un procédé de traitement du diabète de type 2 chez un mammifère. Ce procédé consiste à administrer une quantité efficace sur le plan thérapeutique d'un activateur de protéine kinase activée par AMP au mammifère. Ce dernier peut être, par exemple, un humain, un rat ou une souris. L'activateur de protéine kinase activée par AMP peut être injecté au mammifère par voie sous-cutanée ou administré de toute autre manière permettant l'admission de l'activateur de protéine kinase activé par AMP dans les cellules du mammifère. L'activation de cet activateur de protéine kinase activée par AMP peut produire les avantages de l'exercice physique, y compris la translocation de GLUT4 dans les cellules musculaires du mammifère. Elle concerne également un procédé servant à traiter la résistance à l'insuline chez un mammifère. On administre à ce dernier une quantité efficace sur le plan thérapeutique d'une activateur de protéine kinase activée par AMP.
PCT/US2001/019283 2000-06-16 2001-06-14 Utilisation d'activateurs d'amp kinase pour traiter le diabete de type 2 et la resistance a l'insuline Ceased WO2001097816A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007082309A3 (fr) * 2006-01-16 2007-10-04 Univ Texas Procédés et composition induisant une torpeur chez un sujet
US7560435B2 (en) 2002-03-21 2009-07-14 Advanced In Vitro Cell Technologies, S. A. Therapeutic use of riboside of 5-aminoimidazole-4-carboxamide (acadesine)
US8895520B2 (en) 2011-10-26 2014-11-25 Universite Nice Sophia Antipolis Method for treating a human patent suffering from Myeloid Neoplasias using 5-aminoimidazole-4-carboxamide
WO2020050935A2 (fr) 2018-08-06 2020-03-12 Skylark Bioscience Llc Composés activant la protéine kinase activée par l'amp et leurs utilisations
US11779590B2 (en) 2020-10-30 2023-10-10 Skylark Bioscience Llc AMP-activated protein kinase activating compounds and uses thereof

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US4575498A (en) * 1983-07-21 1986-03-11 Duke University Method for restoring depleted purine nucleotide pools
US4912092A (en) * 1986-03-27 1990-03-27 The Regents Of The University Of California Methods for increasing extracellular adenosine and for stabilizing mast cells
US5082829A (en) * 1989-01-24 1992-01-21 Gensia Pharmaceuticals AICA riboside prodrugs
US5658889A (en) * 1989-01-24 1997-08-19 Gensia Pharmaceuticals, Inc. Method and compounds for aica riboside delivery and for lowering blood glucose
US5777100A (en) * 1990-08-10 1998-07-07 Gensia Inc. AICA riboside analogs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4575498A (en) * 1983-07-21 1986-03-11 Duke University Method for restoring depleted purine nucleotide pools
US4912092A (en) * 1986-03-27 1990-03-27 The Regents Of The University Of California Methods for increasing extracellular adenosine and for stabilizing mast cells
US5082829A (en) * 1989-01-24 1992-01-21 Gensia Pharmaceuticals AICA riboside prodrugs
US5658889A (en) * 1989-01-24 1997-08-19 Gensia Pharmaceuticals, Inc. Method and compounds for aica riboside delivery and for lowering blood glucose
US5777100A (en) * 1990-08-10 1998-07-07 Gensia Inc. AICA riboside analogs

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7560435B2 (en) 2002-03-21 2009-07-14 Advanced In Vitro Cell Technologies, S. A. Therapeutic use of riboside of 5-aminoimidazole-4-carboxamide (acadesine)
WO2007082309A3 (fr) * 2006-01-16 2007-10-04 Univ Texas Procédés et composition induisant une torpeur chez un sujet
US8895520B2 (en) 2011-10-26 2014-11-25 Universite Nice Sophia Antipolis Method for treating a human patent suffering from Myeloid Neoplasias using 5-aminoimidazole-4-carboxamide
WO2020050935A2 (fr) 2018-08-06 2020-03-12 Skylark Bioscience Llc Composés activant la protéine kinase activée par l'amp et leurs utilisations
CN112739352A (zh) * 2018-08-06 2021-04-30 斯凯拉克生物科技有限责任公司 活化amp-活化的蛋白激酶的化合物及其用途
US11834469B2 (en) 2018-08-06 2023-12-05 Skylark Bioscience Llc AMP-activated protein kinase activating compounds and uses thereof
CN112739352B (zh) * 2018-08-06 2024-01-23 斯凯拉克生物科技有限责任公司 活化amp-活化的蛋白激酶的化合物及其用途
US11779590B2 (en) 2020-10-30 2023-10-10 Skylark Bioscience Llc AMP-activated protein kinase activating compounds and uses thereof

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