WO2016196281A1 - Inhibiteurs mtap pour le traitement de la drépanocytose - Google Patents

Inhibiteurs mtap pour le traitement de la drépanocytose Download PDF

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WO2016196281A1
WO2016196281A1 PCT/US2016/034625 US2016034625W WO2016196281A1 WO 2016196281 A1 WO2016196281 A1 WO 2016196281A1 US 2016034625 W US2016034625 W US 2016034625W WO 2016196281 A1 WO2016196281 A1 WO 2016196281A1
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agents
pharmaceutically acceptable
sickle
acceptable salt
sickle cell
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PCT/US2016/034625
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English (en)
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Steven Isaacman
Andrew Mahon
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Nanometics Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to treatments and therapies for anemia conditions and diseases of the blood, and more particular is a therapy for the acute and chronic treatment of sickle cell diseases and thalassemia by administration of an inhibitor of 5'
  • MTAP methylthioadenosine phosphorylase
  • Sickle cell disease is a global health issue that affects over 13 million people worldwide, including ⁇ 100,000 Americans.
  • SCD results from an autosomal recessive red blood cell (RBC) disorder and is most common in populations of African, Mediterranean or Asian ancestry.
  • RBC red blood cell
  • Over 300,000 babies are born each year with the disease.
  • SCD is caused by an inherited hemoglobinopathy that weakens the oxygen binding affinity of hemoglobin (Hb), enabling polymers of deoxyhemoglobin (deoxyHb) to form in the erythrocyte. Consequently, the RBCs become rigid and assume distorted morphologies.
  • Hb hemoglobin
  • deoxyHb deoxyhemoglobin
  • VOC vaso- occlusion
  • Sickle cell disease is a global health issue that affects over 13 million people worldwide, including approximately 100,000 Americans. 6,7 SCD results from an autosomal recessive red blood cell (RBC) disorder and is most common in populations of African, Mediterranean or Asian ancestry. 6,7 Over 300,000 babies are born each year with the disease. 6 The molecular basis for SCD is a 6Glu ⁇ Val mutation, which weakens the affinity of oxygen for hemoglobin (Hb), and enables polymers of deoxyhemoglobin
  • SCD displays pathophysiological characteristics that mimic those of ischemia / reperfusion injury. 10 Chronic hemolytic anemia disrupts the oxidative stress equilibrium of patients, and can trigger inflammatory cascades that result in adhesion of leukocytes to vascular walls, recurrent and intermittent episodes of VOC and painful episodes of crisis. 8, Due to the importance of inflammatory cascades in propagating VOC, many forms of anti-inflammatory therapy are being actively pursued to treat the disease.
  • antiinflammatory approaches include: Regadenoson 12 , an ADORAA2 agonist; statins 13 ; Zieluotn, a 5-lipoxygenase inhibitor ; fructose-1 ,6-phosphate, which reduces ischemia induced tissue damage 15 ; pegylated carboxyhemoglobin 16 , which delivers non-toxic levels of carbon monoxide to reduce inflammation; and, monoclonal antibody therapy to facilitate iNKT cell depletion. 17
  • MTA 5'-Methylthioadenosine
  • BERK Berkley
  • This SBIR project proposes a new anti-inflammatory approach to treat SCD that blocks MTA metabolism at 5'-methylthioadenosine phosphorylase (MTAP), enabling the sustained accumulation of endogenous MTA to th erapeutically beneficial levels.
  • MTAP 5'-methylthioadenosine phosphorylase
  • the present invention overcomes deficiencies of the presently available treatments and therapies by providing a novel therapy for sickle cell diseases, Thalassemia and other related blood diseases (e.g. sickle cell trait) comprising oral administration of a
  • the MTAP inhibitor can be delivered by any means, preferably orally, subcutaneously, or intravenously, and is useful as a chronic treatment and as an acute treatment. Accordingly, the present invention is directed to a method of treating and/or reducing the likelihood of the symptoms of a blood disease, including sickle cell disease, Thalassemia or a related blood discussed comprising administering to a patient in need an effective amount of a MTAP inhibitor or a
  • This application is directed to the use of a small molecule transition state inhibitor of MTAP as therapy for sickle cell disease, including sickle crisis.
  • the sole function of MTAP in mammals is to metabolize MTA, and the systemic inhibition of MTAP causes whole-body accumulation of endogenous MTA to therapeutically beneficial levels (up to 100x in plasma for >24 h).
  • Methylthio-DADMe-lmmucillin-A (MTDIA), is a powerful MTAP inhibitor and was used as a tool to demonstrate the novelty of the Nanometics approach described herein.
  • a single dose of an MTAP inhibitor significantly reduced levels of leukocyte recruitment and endothelial activation in venules to produce hemodynamic parameters that resembled wild type (C57-BL) values.
  • BERK mice are transgenic models of SCD that display severe pathology and similar features to the human disease state including elevated vascular endothelial activation and impaired blood flow.
  • Oxidative stress and nitric oxide (NO) homeostasis are thought to play a major role in the severity of the disease, and agents that modulate these pathways are highly desirable.
  • the multifactorial process, which leads to VOC involves oxidative stress, damages to red blood cells (RBC), inflammation, vascular leukocyte adhesion, coagulation and abnormal rheology, and vascular tone modulation.
  • RBC red blood cells
  • Ameliorating oxidative stress by directly targeting free radicals, reactive carbonyls and other oxidizing species with non-toxic therapeutic agents has tremendous potential as a treatment for SCD.
  • MTAP inhibitors also have potential as an acute therapy for sickle crisis, for which, there are no FDA approved therapeutic options.
  • the present invention relates to compounds according to the chemical structure:
  • X is S-R or R', where R is a d- 3 alkyl group (preferably methyl or ethyl) or a phenyl group and R' is a C C 3 alkyl group,
  • R is S-Me ("MTDIA") and the compound is in the form of a salt, often a phosphate salt.
  • compositions according to the present invention comprise an effective amount of a compound (an MTAP inhibitor) disclosed above in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with another bioactive agent.
  • a pharmaceutically acceptable carrier, additive or excipient optionally in combination with another bioactive agent.
  • pyridoxamine is optionally included with the MTAP inhibitor, further optionally with another bioactive agent as otherwise disclosed herein.
  • the present invention relates to a method of treating sick cell disease, Thalassemia and other related blood diseases in a patient in need thereof comprising administering to said patient an effective amount of an MTAP inhibitor compound, preferably a compound as disclosed hereinabove, optionally in combination with an additional bioactive agent.
  • the present invention provides pharmaceutical compositions comprising (a) a dosage unit of an effective amount ranging from about 1 mg to about 3000 mg of a MTAP inhibitor (often about 1 mg to about 2000mg), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, optionally in combination with an additional bioactive agent, preferably an active agent for treating sickle cell disease, Thalassemia and other related blood diseases as otherwise described herein.
  • a dosage unit of an effective amount ranging from about 1 mg to about 3000 mg of a MTAP inhibitor (often about 1 mg to about 2000mg), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, optionally in combination with an additional bioactive agent, preferably an active agent for treating sickle cell disease, Thalassemia and other related blood diseases as otherwise described herein.
  • additional bioactive agents can include anti-sickling agents, selectin inhibitors, fetal hemoglobin regulators (including fetal hemoglobin inducing agents), agents which inhibit a platelet ADP receptor, agents which increase the affinity of sickle hemoglobin's binding to oxygen, anti-oxidant agents, anti-inflammatory agents, agents that target leukocyte adhesion and anti-platelet agents, among others as described herein.
  • the present invention provides pharmaceutical compositions comprising: (a) MTAP inhibitor or a pharmaceutically acceptable salt thereof; and (b) one or more additional bioactive agents as described herein, preferably a compound selected from the group consisting of fetal hemoglobin-inducing agents, agents that target leukocyte adhesion, anti-inflammatory agents, anti-oxidant agents, anti-platelet agents and anti-sickling agents, among others.
  • the one or more additional bioactive agents are selected from the group consisting of hemoglobin-inducing agents, in particular fetal hemoglobin- inducing agents, but not limited to, hydroxyurea, sodium phenyl butyrate, sodium phenyl acetate, sodium phenyl propionate, or an alternative pharmaceutical salt thereof (as disclosed in United States patent number 5,712,307, which is incorporated by reference herein), cyclic peptides such as FK228 (depsipeptide) and analogs thereof, as disclosed in Anemia 2012; 2012: 428137 (published online May 14, 2012), benzamides (such as MS- 275); non cyclic and cyclic hydroxamates, for example SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A) among others.
  • hemoglobin-inducing agents in particular fetal hemoglobin- inducing agents, but not limited to, hydroxyurea, sodium phenyl butyrate, sodium phenyl
  • the present invention provides methods for treating sickle cell disease and/or complications arising from sickle cell disease including, comprising administering to the human patient an amount of an MTAP inhibitor, or a pharmaceutically acceptable salt thereof, effective to alleviate the physiological manifestations of the disease including, but not limited to, venular occlusion and sickle crisis and chronic and systemic vasculopathies including stroke, sickle retinopathy, open leg ulcers, multi-organ failure, aseptic bone necrosis, dactylitis, hepatopathy, splenic autoinfarction, pulmonary
  • hypertension hypertension, cognitive deficits, renal failure, cholecystitis, decreased fertility, increased susceptibility to infection and decreased opsonization, among others.
  • the present invention provides methods for treating or averting episodes of sickle cell crisis whereby MTAP inhibitor, or a pharmaceutically acceptable salt, is optionally combined with an additional bioactive agent is administered (preferably, orally or by injection) to mitigate the crisis episode.
  • vessel occlusion can also cause chronic and systemic vasculopathies that yield devastating results. These can include: stroke, sickle retinopathy, open leg ulcers, multi-organ failure, aseptic bone necrosis, dactylitis,
  • hydroxyurea In addition to increasing fetal hemoglobin (HbF) levels, hydroxyurea can also increase nitric oxide (NO) levels and has been shown to depress leukocyte counts; decreasing the local inflammatory reaction and increasing mean cell volume.
  • NO nitric oxide
  • the present invention which relies on the use of an MTAP inhibitor, preferably MTDIA, provides for a non-toxic, therapeutic, preferably including an oral therapeutic, that will attenuate ongoing oxidative stress in the microcirculation, improve perfusion to organs, and mitigate the damage to circulating RBC. It is anticipated that the present invention will be useful in both children and adults, as a single agent or as part of a combination therapy. As a prophylactic, it is expected that an MTAP inhibitor, preferably MTDIA, will reduce oxidative stress mediated complications in the microcirculation, hence improving vascular and organ health in SCD patients.
  • Oxidative stress is a major driver of the pro-inflammatory state associated with SCD.
  • Oxidative stress is a major driver of the pro-inflammatory state associated with SCD.
  • Higher rates of autoxidation of HbS in vivo, RBC damage and lysis, cell free hemoglobin, ischemia-reperfusion injury and inflammation all contribute to increased levels of oxidants, which perpetuate the pro-inflammatory state.
  • Cell free hemoglobin as a result of chronic hemolysis, reduces nitric oxide (NO) bioavailability, which has vasoconstrictive,
  • MTA The potent anti-inflammatory profile of MTA was demonstrated in a number of preclinical models.
  • LPS lipopolysaccharide
  • TNF-a tumor necrosis factor-alpha
  • IKBa Inhibitors of Kappa B-alpha
  • NFKB Nuclear Factor-KB
  • MTA pharmacokinetics
  • 21 MTAP rapidly metabolizes MTA in vivo with excess MTA cleared renally, as demonstrated by high urine concentrations of MTA in exploratory PK experiments (data not shown).
  • the present inventors' approach utilizes a single dose of
  • MTDIA methylthioDADMe-lmmucillin-A
  • An oral or i.p. dose of MTDIA inhibits MTAP activity in vivo for >24 h and results in whole-body accumulation of MTA in plasma to >100-fold higher than baseline levels (Preliminary Results).
  • a single i.p. dose of MTDIA given to BERK mice improved endothelial function and ameliorated the endothelial activation that is associated with venular occlusion and episodes of sickle crisis.
  • Figure 1 shows the schematic representation of intravital microscopy protocols
  • MTDIA 15mg/kg, gavage
  • time -21 hr the surgical preparation of cremasteric muscle for intravital microscopy
  • images of the cremasteric venules under intravital microscopy were recorded between the time points of 1 and 2 hr.
  • a single dose of MTDIA (15mg/kg, oral gavage, 24 hr prior) improves blood flow rate (a) and reduces leukocyte adhesion (b) in BERK mice (normoxia) and in BERK mice challenged with hypoxia/reoxygenation (H/R).
  • H/R challenge did not further reduce blood flow rate or further increase leukocyte adhesion in BERK mice (both blood flow rate and number of adherent leukocyte are comparable between normoxia and H/R-challenged BERK mice).
  • MTDIA treatment did not alter (c) the systemic white blood cell (WBC) and (d) did not significantly change the number of emigrated leukocytes in the area adjacent to the postcapillary venules in the cremaster muscle of BERK mice during the time frame of our experiment.
  • RBC red blood cell
  • Hgb hemoglobin concentration
  • Hct hematocrit
  • patient or “subject” is used throughout the specification within context to describe an animal, generally a mammal, especially including a human, to whom treatment, including prophylactic treatment (prophylaxis), with the compounds or compositions according to the present invention is provided.
  • treatment including prophylactic treatment (prophylaxis), with the compounds or compositions according to the present invention is provided.
  • patient refers to that specific animal.
  • the patient or subject of the present invention is a human patient of either or both genders.
  • the patient is resistant to therapy with hydroxyurea.
  • hydroxyurea may be co-administered with the MTAP inhibitor (preferably MTDIA) to effect therapy in the patient.
  • MTAP inhibitor preferably MTDIA
  • prophylactic or “prophylaxis” shall mean preventing or reducing the likelihood that a disease, condition or event will occur.
  • compound is used herein to describe any specific compound or bioactive agent disclosed herein, including any and all stereoisomers (including diasteromers) if applicable, individual optical isomers (enantiomers) or racemic mixtures, pharmaceutically acceptable salts, prodrug forms, including hydrates and solvates of these compounds.
  • compound herein refers to stable compounds. Within its use in context, the term compound may refer to a single compound or a mixture of compounds as otherwise described herein.
  • bioactive agent refers to any biologically active compound or drug which may be formulated for use in an embodiment of the present invention.
  • exemplary bioactive agents include the compounds according to the present invention which are used to treat sick cell anemia, Thallesemia or a disease state or condition which occurs secondary to sick cell anemia, thallesemia or and other related blood diseases as well as other compounds or agents which are otherwise described herein.
  • Bioactive agents for use in the present invention include anti-sickling agents, selectin and adhesion inhibitors, fetal hemoglobin regulators, agents which inhibit a platelet ADP receptor and other anti-platelet agents, agents which increase the affinity of sickle hemoglobin's binding to oxygen, antioxidants, nitric oxide generating agents, vascular tone agents and anti-inflammatory agents and agents that target leukocyte adhesion, among others.
  • a fetal hormone regulator includes hemoglobin-inducing agents, in particular fetal hemoglobin- inducing agents.
  • bioactive agents which can be coadministered with the MTAP inhibitor (preferably MTDIA) or a pharmaceutically acceptable salt thereof.
  • anti-sickling agents 5-hydroxymethylfurfural, 4-Hydroxy-3-methoxybenzaldehyde.
  • selectin and adhesion inhibitors GMI-1070, GMI-1271 , intravenous immunoglobulin, tinzaparin, propranolol, SelG1 (humanized anti p-selectin antibody), heparin.
  • fetal hemoglobin regulators include hemoglobin inducing agents: hydroxyurea, decitabine, sodium dimethylbutyrate, pomalidomide, (2E)-N-hydroxy-3-[4-( ⁇ [2-(2-methyl-1 H- indol-3-yl)ethyl]amino ⁇ methyl)phenyl]acrylamide, sodium phenyl butyrate, sodium phenyl acetate, sodium phenyl propionate, or an alternative pharmaceutical salt thereof (as disclosed in United States patent number 5,712,307, which is incorporated by reference herein), cyclic peptides such as FK228 (depsipeptide) and analogs thereof, as disclosed in Anemia 2012; 2012: 428137 (published online May 14, 2012), benzamides (such as MS- 275); non cyclic and cyclic hydroxamates, for example SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A) among others.
  • SAHA suberoylanil
  • agents which inhibit a platelet ADP receptor (f?,S)-5-[2-cyclopropyl-1-(2-fluorophenyl)-2- oxoethyl] 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate, N-hydroxy-N'-phenyl- octanediamide.
  • agents which increase the affinity of sickle hemoglobin's binding to oxygen 5- hydroxymethylfurfural, pyridoxal-5-phosphate, 4-hydroxy-3-methoxybenzaldehyde.
  • antioxidants including, but not limited to, para-aminobenzoic acid (PABA), pyridoxine, pyridoxine-5-phosphate, pyridoxal-5-phosphate, ascorbic acid, W-acetyl cysteine, a-linolenic acid, eicosapentaenoic acid, docosahexanoc acid, glutamine, acetyssl-L-carnitine.
  • PABA para-aminobenzoic acid
  • pyridoxine pyridoxine-5-phosphate
  • pyridoxal-5-phosphate ascorbic acid
  • W-acetyl cysteine a-linolenic acid
  • eicosapentaenoic acid docosahexanoc acid
  • glutamine acetyssl-L-carnitine.
  • Nitric oxide generating agents L-Arginine.
  • Vascular tone agents intravenous magnesium.
  • Anti-inflammatory agents 2- ⁇ 4-[(methylamino)carbonyl]- 1 H-pyrazol-1-yl ⁇ adenosine, N-[1- (1-benzothien-2-yl)ethyl]-N-hydroxyurea, Fructose-1 ,6-diphosphate, oxooxan-2-yl]ethyl ⁇ -3,7- dimethyl-1 ,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate, 2-acetoxybenzoic acid.
  • treat is used synonymously to refer to any action providing a benefit to a patient at risk for or afflicted with a disease state or condition as described herein, including improvement in the disease state or condition through lessening, inhibition, suppression or elimination of at least one symptom, delay in progression of the disease, prevention, delay in or inhibition of the likelihood of the onset of the disease or condition, etc.
  • Treatment encompasses both prophylactic and therapeutic treatment, principally of sickle cell diseases, Thalassemia and other related blood diseases, as well as secondary disease states and conditions such as vessel occlusion, chronic and systemic vasculopathies, as well as stroke, sickle retinopathy, open leg ulcers, multi-organ failure, aseptic bone necrosis, dactylitis, hepatopathy, splenic autoinfarction, pulmonary infections
  • Compounds according to the present invention can, for example, be
  • Prophylactically administered prophylactically to a patient in advance of the occurrence of a disease state or condition to reduce the likelihood of that disease state or condition.
  • administration is effective to reduce or decrease the likelihood of the subsequent occurrence of disease in the patient, or decrease the severity of the disease state or condition that subsequently occurs, especially including secondary disease states or conditions.
  • compounds according to the present invention can, for example, be
  • administration of the present compounds is effective to eliminate the disease and substantially eliminate the likelihood of further manifestations of disease.
  • Administration of the compounds according to the present invention is effective to decrease the severity of the disease or lengthen the lifespan of the mammal so afflicted, or inhibit or even eliminate the causative agent of the disease.
  • pharmaceutically acceptable means that the compound or composition is suitable for administration to a subject, including a human patient, to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • inhibitor refers to the partial or complete elimination of a potential effect, while inhibitors are compounds/compositions that have the ability to inhibit.
  • prevention or “prophylactic” when used in context shall mean “reducing the likelihood” of preventing a disease, condition or disease state from occurring as a
  • prophylaxis will rarely be 100% effective; consequently the terms prevention and reducing the likelihood are used to denote the fact that within a given population of patients or subjects, administration with compounds according to the present invention will reduce the likelihood or inhibit a particular condition or disease state (in particular, the worsening of a disease state such as the growth or metastasis of cancer) or other accepted indicators of disease progression from occurring.
  • administer and “coadministration” are used synonymously to describe the administration of MTAP inhibitor, preferably MTDIA and at least one additional bioactive agent (as otherwise described herein), which are administered in amounts or at
  • compositions/agents which would be considered to be effective amounts at or about the same time. While it is preferred that coadministered compositions/agents be administered at the same time, agents may be administered at different times such that effective concentrations of both (or more) compositions/agents appear in the patient at the same time for at least a brief period of time. Alternatively, in certain aspects of the present invention, it may be possible to have each coadministered composition/agent exhibit its inhibitory effect at different times in the patient, with the ultimate result being the inhibition and treatment of sickle cell disease, Thalassemia or a related blood disease or disorder or a secondary disease state or condition thereof. Of course, when more than disease state or condition is present, the present compounds may be combined with other agents to treat that other disease state or condition as required.
  • SCD sickle cell disease
  • Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate. These include sickle cell crisis, vaso-occlusive crisis, splenic sequestration crisis, acute chest syndrome (ACS), aplastic crisis, haemolytic crisis, dactylitis, increased risk of severe bacterial infections, especially Streptococcus pneumonia and Haemophilus influenza, due to loss of functioning spleen tissue, stroke, cerebral infarction in children, cerebral haemorrhage in adults, silent stroke, causing no outward symptoms but associated with damage to the brain, cholelithiasis (gallstones) and cholecystitis, avascular necrosis (aseptic bone necrosis) of the hip and other major joints, decreased immune reactions due to hyposplenism, priapism, osteomyletis (bacterial bone infection, often from Salmonella), acute papillary necrosis (kidneys), leg ulcers, eye complications (background retinopathy, proliferative reti
  • Thalassemia is used herein to describe an inherited blood disorder in which the body makes an abnormal form of hemoglobin resulting in less hemoglobin than normal and far fewer circulating red blood cells, resulting in a mild or severe anemia. Thalassemia is often present as microcytic anemia. Thalassemia can cause significant complications, including iron overload, an enlarged spleen, susceptible to illness, bone deformities and cardiovascular illness, each of which may be improved and/or resolved by treatment of principal disease state. Thalassemia may confer a level of protection against malaria.
  • sickle cell trait is used herein to describe a condition in which a person has one abnormal allele of the hemoglobin beta gene (is heterozygous), but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele (is homozygous).
  • Sickle cell disease can be cured using hematopoietic stem cell transplants, and the severity of the disease can be reduced with repeated transfusions.
  • SCD Sickle cell disease
  • HU hydroxyurea
  • HbF fetal Hb
  • Proper use of HU requires strict compliance; self-administration by the patient; and careful monitoring by the physician to ensure proper dosing schedules.
  • HbF fetal Hb
  • the chronic hemolytic anemia disrupts the oxidative stress equilibrium of patients, and can trigger inflammatory cascades that result in adhesion of leukocytes to vascular walls, recurrent and intermittent episodes of vaso-occlusion (VOC) and painful episodes of crisis.
  • VOC vaso-occlusion
  • the pain associated with crisis can be debilitating, and lead to hospitalization.
  • Oxidative stress and NO homeostasis are thought to play a major role in the severity of the disease, and agents that modulate these pathways are highly desirable.
  • the multifactorial process, which leads to VOC involves oxidative stress, damages to red blood cells (RBC), inflammation, vascular leukocyte adhesion, coagulation and abnormal rheology, and vascular tone modulation.
  • RBC red blood cells
  • fetal hemoglobin-inducing agents include: fetal hemoglobin-inducing agents, agents that target leukocyte adhesion, anti-inflammatory agents, anti-oxidant therapies, anti-platelet therapies and anti-sickling approaches.
  • Another therapy, pyridoxamine is unique in that it is a well-tolerated vitamer of the B6 family, and has been studied extensively in humans. Preliminary results suggest that pyridoxamine is multimodal; disrupting molecular mechanisms of the vaso-occlusion (VOC) cascade, and simultaneously facilitating oxygen delivery to the brain. Many of the emerging therapies target the VOC cascade, and are predominantly anti-inflammatory approaches.
  • the MTAP inhibitor preferably MTDIA, as its pharmaceutically acceptable salt, will be useful as a single agent, or as part of a combination therapy (co-administration approach) to treat sickle cell disease.
  • compositions comprising (a) MTAP inhibitor, or a pharmaceutically acceptable salt thereof; and (b) one or more compounds that can provide benefit in a human patient, or
  • such compounds are selected from the group consisting of fetal hemoglobin-inducing agents as otherwise described herein, agents that target leukocyte adhesion, anti-inflammatory agents, antioxidant therapies, anti-platelet therapies or anti-sickling therapeutics.
  • pyridoxamine is co-administered with hydroxyurea.
  • Pharmaceutically acceptable salts in accordance with the present invention include salts with physiologically acceptable bases and/or acids well known to those skilled in the art of pharmaceutical technique.
  • Suitable salts with physiologically acceptable bases include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts with suitable organic bases, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and triethanolamine.
  • Suitable salts with physiologically acceptable acids include, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides), sulphates and phosphates, and salts with organic acids. Phosphate salts of MTDIA are preferred.
  • the pharmaceutical compositions of this aspect of the invention include admixtures of the MTAP inhhibitor, or pharmaceutically acceptable salt thereof, and the one or more other
  • Such separate unit dosages may be administered concurrently or sequentially as determined by the clinician.
  • the compounds are combined with one or more pharmaceutically acceptable carriers, excipients and/or additives appropriate for the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the pharmaceutical compositions of the invention are prepared for oral administration.
  • the pharmaceutical composition can be in the form of, for example, a tablet, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a liquid, or any other form reasonably adapted for oral administration.
  • the pharmaceutical compositions can further comprise, for example, buffering agents. Tablets, pills and the like additionally can be prepared with enteric coatings. Unit dosage tablets or capsules are preferred.
  • Pharmaceutical compositions suitable for buccal administration include, for example, lozenges comprising a MTAP inhibitor or a pharmaceutically acceptable salt thereof and a flavored base, such as sucrose, acacia tragacanth, gelatin, and/or glycerin.
  • Liquid dosage forms for oral administration can comprise pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise, for example, wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • compositions according to the present invention comprise an effective amount of MTAP inhibitor or a pharmaceutically acceptable salt, optionally in combination with an additional bioactive agent as otherwise described herein (which may include pyridoxamine) formulated to effect an intended result (e.g. therapeutic and/or prophylactic result) formulated in combination with a pharmaceutically acceptable carrier, additive or excipient.
  • additional bioactive agent as otherwise described herein (which may include pyridoxamine) formulated to effect an intended result (e.g. therapeutic and/or prophylactic result) formulated in combination with a pharmaceutically acceptable carrier, additive or excipient.
  • Pharmaceutical compositions according to the present invention may also comprise an addition bioactive agent or drug as otherwise described herein.
  • compositions may be administered to a subject by various routes, e.g. orally, transdermal ⁇ , topically, perineurally or parenterally, that is, by intravenous, subcutaneous, intraperitoneal, intrathecal or intramuscular injection, among others, including buccal, rectal and transdermal administration.
  • routes e.g. orally, transdermal ⁇ , topically, perineurally or parenterally, that is, by intravenous, subcutaneous, intraperitoneal, intrathecal or intramuscular injection, among others, including buccal, rectal and transdermal administration.
  • Compositions may be administered by inhalation dosage form to the lungs, trachea, nasal passages, mouth, etc.
  • Subjects contemplated for treatment according to the method of the invention include humans, companion animals, laboratory animals, and the like.
  • the invention contemplates immediate and/or sustained/controlled release compositions, including compositions which comprise both immediate and sustained release formulations. This is particularly true when one or more different bioactive agents are used in the pharmaceutical compositions in combination with MTAP inhibitor or its pharmaceutically acceptable salt as otherwise described herein.
  • Formulations containing the compounds according to the present invention may take the form of liquid, solid, semi-solid or lyophilized powder forms, such as, for example, solutions, suspensions, emulsions, sustained-release formulations, tablets, capsules, powders, suppositories, creams, ointments, lotions, aerosols, patches or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions according to the present invention typically include a conventional pharmaceutical carrier, excipient and/or additive and may additionally include other medicinal agents, adjuvants and the like.
  • the composition is about 0.1 % to about 85%, about 0.5% to about 75% by weight of an MTAP inhibitor or its salt and optionally, an additional bioactive agent, with the remainder of the composition consisting essentially of suitable pharmaceutical excipients.
  • An injectable composition for parenteral administration will typically contain the compound in a suitable i.v. solution, such as sterile physiological salt solution.
  • the composition may also be formulated as a suspension in an aqueous emulsion.
  • Liquid compositions can be prepared by dissolving or dispersing the active agent(s) (about 0.5% to about 20% by weight or more), and optional pharmaceutical adjuvants, in a carrier, such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension.
  • a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension.
  • the composition may be prepared as a solution, suspension, emulsion, or syrup, being supplied either in liquid form or a dried form suitable for hydration in water or normal saline.
  • excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like, as described.
  • the composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or buffers.
  • the preparations may be tablets, granules, powders, capsules or the like.
  • the composition is typically formulated with additives, e.g. an excipient such as a saccharide or cellulose preparation, a binder such as starch paste or methyl cellulose, a filler, a disintegrator, and other additives typically used in the manufacture of medical preparations.
  • additives e.g. an excipient such as a saccharide or cellulose preparation, a binder such as starch paste or methyl cellulose, a filler, a disintegrator, and other additives typically used in the manufacture of medical preparations.
  • compositions to be administered will contain a quantity of the selected compound in a pharmaceutically effective amount for therapeutic use in a patient according to the present invention.
  • These pharmaceutical compositions can be prepared by any suitable method that includes the step of bringing into association pyridoxamine, or a pharmaceutically acceptable salt thereof (and optionally the other compounds) and the pharmaceutically acceptable carrier.
  • the compositions are prepared by uniformly and intimately admixing the MTAP inhibitor, or a pharmaceutically acceptable salt thereof, with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • preparation of tablets can comprise compressing or molding a powder or granule of the compound.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binding agent, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
  • the present invention provides methods for limiting the progression of end organ disease and/or complications in a human patient with sickle cell disease by administering to the patient an amount of a MTAP inhibitor, or a pharmaceutically acceptable salt thereof, effective to limit the progression of end organ disease or complications in the sickle cell disease patient.
  • the methods comprise administering the pharmaceutical compositions of the invention to the patient.
  • one embodiment of the method comprises administering between about 500 pg and 2500mg, more often about 1 mg to about 2000 milligrams of a MTAP inhibitor (preferably MTDIA), or a pharmaceutically acceptable salt thereof, to the patient, more preferably between about 5 and 1000 milligrams of a MTAP inhibitor, preferably MTDIA, or a pharmaceutically acceptable salt thereof, optionally in combination with an additional bioactive agent.
  • a MTAP inhibitor preferably MTDIA
  • a pharmaceutically acceptable salt thereof optionally in combination with an additional bioactive agent.
  • Preliminary studies tested the hypothesis that systemic MTAP inhibition, and the subsequent increase in whole-body MTA levels, would be non-toxic in mice and convey therapeutic benefits in BERK models of SCD. All studies were conducted with the phosphate salt of MTDIA. i. A single oral dose of MTDIA alleviates endothelial activation in BERK mouse models of SCD: Knockout Berkley (BERK) mice express 100% human hemoglobin a-subunit, >99% human hemoglobin s -subunit and similar pathologies to humans with SCD. Characteristic pathologies include anemia, hemolysis, reticulocytosis, low hematocrit, and extensive multiple organ damage.
  • Vascular obstruction is thought to occur primarily as a result of interactions between adherent leukocytes, in postcapillary and collecting venules, and circulating RBCs.
  • 24 BERK mice display elevated levels of leukocyte recruitment to the vascular endothelium, which is detrimental to blood rheology and a key contributor to disease pathology.
  • Intravital microscopic analysis of cremastic venules 4h after a single i.p. dose of MTDIA was used to determine the effect of MTDIA on leukocyte recruitment and hemodynamic properties in BERK mice.
  • a single i.p. dose of MTA (15 - 100 mg/kg) did not induce any measurable changes in these parameters (data not shown).
  • MTDIA significantly decreased the number of rolling leukocytes, as defined by the total number of rolling leukocytes (stationary on vessel walls f or ⁇ 40 sec) per 100 ⁇ of vessel observed.
  • Sickle red blood cells sRBCs primarily interact with adherent leukocytes and the number of adherent leukocytes was dramatically reduced to near wild-type levels.
  • Leukocytes were considered adherent when observed stationary on vessel walls >40 sec.
  • Leukocyte emigration was also significantly reduced in these studies, which indicates a reduced inflammatory response. Improvements in RBC velocity, and shear rate were also noted. Venule diameter remained constant, indicating that
  • Figure 1 shows the schematic representation of intravital microscopy protocols
  • MTDIA 15mg/kg, gavage
  • time -21 hr the surgical preparation of cremasteric muscle for intravital microscopy
  • images of the cremasteric venules under intravital microscopy were recorded between the time points of 1 and 2 hr.
  • mice 15mg/kg, gavage was administered to BERK sickle mice 16 hours (time -16hr) prior to placing the mice in 8% 0 2 (balanced with N 2 ) hypoxia chamber (time 0). After 3 hours in hypoxia chamber, mice were returned to ambient air for a total of 4 hours (reoxygenation). Exteriorization of cremasteric muscle and imaging/recording of cremasteric microcirculation were carried out during the 4hr-reoxygenation period.
  • a single dose of MTDIA (15mg/kg, oral gavage, 24 hr prior) improves blood flow rate (a) and reduces leukocyte adhesion (b) in BERK mice (normoxia) and in BERK mice challenged with hypoxia/reoxygenation (H/R).
  • H/R challenge did not further reduce blood flow rate or further increase leukocyte adhesion in BERK mice (both blood flow rate and number of adherent leukocyte are comparable between normoxia and H/R-challenged BERK mice).
  • MTDIA treatment did not alter (c) the systemic white blood cell (WBC) and (d) did not significantly change the number of emigrated leukocytes in the area adjacent to the postcapillary venules in the cremaster muscle of BERK mice during the time frame of our experiment.
  • RBC red blood cell
  • Hgb hemoglobin concentration
  • Hct hematocrit
  • Singh V. et al. Picomolar transition state analogue inhibitors of human 5'- methylthioadenosine phosphorylase and X-ray structure with MT-immucillin-A.

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Abstract

La présente invention concerne des traitements et des thérapies pour des états d'anémie et des maladies du sang, et plus particulièrement, une thérapie pour les états aigus et chroniques de la drépanocytose et des thalassémies par administration d'un inhibiteur de 5'-méthylthioadénosine phosphorylase, ou un de ses sels pharmaceutiquement acceptables, éventuellement en combinaison avec un agent bioactif supplémentaire.
PCT/US2016/034625 2015-06-01 2016-05-27 Inhibiteurs mtap pour le traitement de la drépanocytose WO2016196281A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114341368A (zh) * 2019-07-12 2022-04-12 糖模拟物有限公司 使用基因表达作为多种肿瘤类型的e-选择素抑制剂功效和临床结果的指标的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5108754A (en) * 1991-02-08 1992-04-28 Michael Wilburn Orthomolecular method of treating sickle cell disease
US20040110772A1 (en) * 2002-03-25 2004-06-10 Furneaux Richard Hubert Inhibitors of nucleoside phosphorylases and nucleosidases
US20110092521A1 (en) * 2006-02-24 2011-04-21 Richard Hubert Furneaux Methods of Treating Diseases Using Inhibitors of Nucleoside Phosphorylases and Nucleosidases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5108754A (en) * 1991-02-08 1992-04-28 Michael Wilburn Orthomolecular method of treating sickle cell disease
US20040110772A1 (en) * 2002-03-25 2004-06-10 Furneaux Richard Hubert Inhibitors of nucleoside phosphorylases and nucleosidases
US20110092521A1 (en) * 2006-02-24 2011-04-21 Richard Hubert Furneaux Methods of Treating Diseases Using Inhibitors of Nucleoside Phosphorylases and Nucleosidases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114341368A (zh) * 2019-07-12 2022-04-12 糖模拟物有限公司 使用基因表达作为多种肿瘤类型的e-选择素抑制剂功效和临床结果的指标的方法

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