WO2011150067A1 - Traitement des anomalies de taux de lipides sanguins et d'autres états - Google Patents

Traitement des anomalies de taux de lipides sanguins et d'autres états Download PDF

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Publication number
WO2011150067A1
WO2011150067A1 PCT/US2011/037912 US2011037912W WO2011150067A1 WO 2011150067 A1 WO2011150067 A1 WO 2011150067A1 US 2011037912 W US2011037912 W US 2011037912W WO 2011150067 A1 WO2011150067 A1 WO 2011150067A1
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concentration
fasting
cholesterol
blood
reducing
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PCT/US2011/037912
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English (en)
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Derek Nunez
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Glaxosmithkline Llc
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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
    • A61K31/33—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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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

Definitions

  • the present invention relates to a method for treating a disease or condition in a human, which method comprises administering 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4- oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof to a human in need thereof.
  • Coronary artery disease is the leading cause of morbidity and mortality in an industrialized society, and blood lipid abnormalities are the major risk factors for CAD.
  • CAD Coronary artery disease
  • Atherosclerosis is the leading cause of morbidity and mortality in the industrialized world because it is the underlying mechanism leading to CAD, cerebrovascular stroke, and peripheral vascular disease.
  • the later stages of atherosclerosis are characterized by lipid filled plaques in the vessel wall that can narrow the arterial lumen and limit blood flow.
  • macrophage foam cells in the plaques have taken up cholesterol esters from lipoprotein particles, especially low and intermediate density lipoproteins (LDL and IDL, respectively), and are prone to necrosis, releasing cholesterol and related lipids, enzymes and other materials into the plaque core.
  • LDL and IDL low and intermediate density lipoproteins
  • High density lipoproteins are thought to confer protection against atherosclerosis by removing cholesterol from plaques, a process called reverse cholesterol transport, and perhaps by reducing inflammation in the blood vessel wall.
  • the progression of atherosclerosis in an artery requires both the presence of local damaging factors that lead to the accumulation of macrophages and inflammatory cells, and the dysfunctional delivery or removal of lipids from the plaques.
  • the dysregulation of lipoprotein metabolism, including the overproduction, defective removal or dysfunction of lipoproteins is referred to as dyslipidemia.
  • Dyslipidemias commonly manifest in one or more of a variety of ways, including but not limited to, elevated total cholesterol, elevated LDL cholesterol, reduced HDL cholesterol, and/or elevated triglycerides, as well as different combinations of these abnormalities.
  • the lipoproteins contain proteins that are called apolipoproteins which have several functions, including but not limited to, receptor binding, cholesterol ester/triglyceride transfer and esterification of cholesterol.
  • apolipoprotein B100 apoBIOO
  • apoB100 is associated with the LDL and related non-HDL lipid particles in a 1 :1 stoichiometry, so that the number of apoB100 proteins in the blood is a good measure of the number of non-HDL particles that are associated with atherosclerosis.
  • Most of the apolipoprotein B measured in human blood is in the apoBIOO form.
  • novel therapies that can lower blood LDL, apoBIOO, total cholesterol, and triglycerides and/or raise HDL cholesterol offer an opportunity to provide substantial clinical benefits when used alone or to complement the effects of existing medicines that treat blood lipid abnormalities such as dyslipidemias.
  • HCV hepatitis C virus
  • HCV circulates in blood as a heterogeneous population of lipoviroprotein particles. These low-density highly infectious HCV particles are released from liver cells and are composed of triglyceride-rich lipoproteins containing apoBIOO and
  • apolipoprotein E apolipoprotein E
  • viral nucleocapsids viral nucleocapsids
  • envelope glycoproteins envelope glycoproteins.
  • HCV gains entry into liver cells using a number of "attachment” and ingress routes including the LDL-Receptor (LDL-R) which binds apoBIOO.
  • LDL-R LDL-Receptor
  • novel therapies that can lower non-HDL cholesterol, apoB/BIOO, apoB/B100:apo A1 ratio, and triglycerides offer an opportunity to substantially reduce the HCV load in blood, reduce the infection of new hepatocytes, and treat this chronic and debilitating disease.
  • Obesity, type 2 diabetes, and related metabolic disorders are associated with accumulation of fat in the liver that can eventually damage hepatocytes, producing increases in liver-associated enzymes such as alanine aminotransferase, (also called serum glutamic pyruvic transaminase or alanine transaminase).
  • liver-associated enzymes such as alanine aminotransferase, (also called serum glutamic pyruvic transaminase or alanine transaminase).
  • This non-alcoholic fatty liver disease can progress to complications such as steatohepatitis, fibrosis, cirrhosis, and potentially to hepatocellular carcinoma.
  • the huge increase in the incidence and prevalence of these metabolic disorders has led to an unprecedented number of cases of non-alcoholic fatty liver disease.
  • Non-alcoholic fatty liver disease often presents late when a blood test taken for other reasons reveals abnormalities in the levels of liver-related enzymes, such as alanine aminotranferase. In many of these cases, the complications are established and difficult to reverse by the time the diagnosis is made. Novel therapies that can reduce fat accumulation in the liver and/or reduce plasma alanine aminotransferase offer an opportunity to substantially reduce the burden of non-alcoholic fatty liver disease and its complications when used alone or to
  • Hyperuricemia is associated with an increased risk of gout, tophi, joint disease, renal stones, and impaired renal function.
  • the elevated blood uric acid can result from a genetic predisposition, as well as from the excessive breakdown of cells that occurs when leukemias, lymphomas, and malignant conditions are treated with cancer therapy.
  • hyperuricemia has been linked to the metabolic syndrome of insulin resistance and increased cardiovascular risk, and non-clinical data indicate that high blood levels of uric acid can cause insulin resistance, inflammation in fat tissues and even increased blood pressure.
  • the available treatments for hyperuricemia are associated with side effects, and not all subjects can be treated with sufficient doses of the drugs to prevent the damaging effects of high blood uric acid.
  • new treatments for lowering high blood uric acid have the potential alone or in combination to treat the consequences that can be painful and debilitating.
  • Such disadvantages may include poor response to the treatment, a prolonged course of therapy and a range of side effects including, but not limited to, allergic reactions, blood disorders, liver abnormalities, kidney failure, gastrointestinal discomfort, joint and/or muscle ache, fever, tiredness/fatigue, weakness, nausea, anxiety, depression, suicidal ideation, insomnia, and lightheadedness.
  • the present invention provides a method for treating a human suffering from an abnormality of blood lipids wherein said method comprises administering a
  • composition comprising 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof to a human in need thereof.
  • An example of a blood lipid abnormality is dyslipidemia.
  • the invention further provides a method of treating a disease or condition that would benefit from at least one of the following effects: increasing fasting HDL cholesterol, reduced fasting LDL cholesterol, reducing fasting non-HDL cholesterol, reducing fasting total cholesterol, reducing fasting total cholesterol:HDL cholesterol ratio, reducing fasting LDL cholesterol:HDL cholesterol ratio, reducing fasting and prandial triglycerides, reducing fasting ApoB/B100, reducing fasting ApoB/B100:ApoA1 ratio, reducing fasting ApoE, reducing plasma alanine aminotransferase (also called serum glutamic pyruvic transaminase or alanine transaminase), or reducing plasma uric acid, wherein said method comprises the administration of a pharmaceutical
  • composition comprising 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof to a human in need thereof.
  • a method for treating a disease or condition comprising an abnormality of blood lipids comprising the administration of a pharmaceutical composition comprising 5-[( ⁇ 1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof to a human suffering from dyslipidemia.
  • Figure 7 Change from baseline (Day 1 pre-dose) of plasma alanine
  • Negative values indicate a reduction in concentration compared to baseline.
  • Figure 8 Change from baseline (Day 1 pre-dose) of plasma uric acid for the 300mg BID treatment group in Study 1. Each line represents data from an individual subject. (Y-Axis: Units in mol/L; X-Axis in Days). (Note: Day 15 is approximately 12h after the last dose; after completion of 14 days of dosing). Negative values indicate a reduction in concentration compared to baseline.
  • a method for treating a human suffering from an abnormality of blood lipids comprising administering a pharmaceutical composition of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof to a human in need thereof.
  • the method of treatment of the present invention is for the benefit of a patient suffering from at least one blood lipid abnormality, and/or elevated blood alanine amiinotransferase concentration and/or elevated blood uric acid
  • the compound employed in the method of treatment of the invention is 5-[( ⁇ 1-[3- (1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine.
  • This compound may be referred to herein as GSK 1292263 or GSK 263, or '263.
  • the compound or salt of the method may be administered in the form of a pharmaceutical composition or formulation.
  • a pharmaceutical composition may employ one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • the carrier(s), diluents(s), and excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • composition can be made by any method described in WO
  • the pharmaceutical composition may be adapted to any route as disclosed in WO 2008/070692, preferably it is administered orally. Preferably, it is adapted for oral administration as a tablet or capsule or microencapsulated.
  • a therapeutically effective amount of the compound or salt of the compound of the present invention will depend on a number of factors. Such factors may include the age, weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration. The therapeutically effective amount ultimately is at the discretion of the attendant physician.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound itself.
  • 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof is administered as an oral pharmaceutical composition in a sufficient amount to achieve a level of fasting total plasma or serum cholesterol of less than 200 mg per deciliter and/ or fasting plasma or serum apoB100 of less than 0.6 mg per deciliter, and/ or fasting plasma or serum apoB/apoB100:apoA1 ratio of less than 1 , and/or fasting plasma or serum LDL cholesterol of less than 160 mg per deciliter, and/or fasting plasma or serum non-HDL cholesterol of less than 160 mg per deciliter, and/or fasting plasma orserum triglycerides of less than 400 mg per deciliter and/or fasting plasma or serum HDL cholesterol of greater than 45 mg per deciliter, and/or plasma or serum alanine
  • the compound or a salt of the compound of this invention may be employed alone or in combination with other therapeutic agents.
  • the compound or salt of the compound of this invention may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amount of the compound or salt of the compound of the invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • administration of the combination may be concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be
  • Such current therapeutic agents can include, but are not limited to, statins (3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors), ezetimibe, fibrates (peroxisome proliferator activated receptor alpha agonists) including, but not limited to, fenofibric acid, bezafibrate, gemfibrozil, niacin/nicotinic acid, intestinal bile acid sequestrants, intestinal lipase inhibitors, interferons, ribavirin, allupurinol, corticosteroids, non-steriodal anti-inflammatory drugs, acetaminophen, febuxostat, colchicine, probenecid, metformin, thiazolidinediones, and/or vitamin E.
  • statins 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors)
  • ezetimibe fibrates (peroxisome
  • the method of treatment of the present invention may be employed or be used in other diseases or conditions exhibiting abnormality of blood lipids, and/or blood alanine aminotransferase concentration and/or blood uric acid concentration.
  • diseases or conditions can include, for example, atherosclerotic cardiovascular disease, nonalcoholic fatty liver disease, chronic hepatitis C virus infection, and hyperuricemia.
  • the compound or a salt thereof employed in the method of the invention may be useful in slowing the progression of the cardiovascular diseases or risk of the diseases set forth below.
  • 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof is employed to treat atherosclerotic cardiovascular disease.
  • cardiovascular disease treatment can include, but is not limited to:
  • renal artery disease including impairment of renal function and/or risk of end-stage renal disease and dialysis
  • iliofemoral artery disease such as , for example, intermittent claudication and/or leg gangrene and/or amputation
  • mesenteric artery disease as manifested by, for example, risk of ischemic enteritis and/or colitis and risk of bowel resection for gangrene; e. reduction of need for revascularization procedures of arteries in (a)-(d) above; and
  • the compound or salt thereof of the inventive method herein may play a role with respect to the treatment of HCV since this virus circulates in the blood as triglyceride- rich lipoproteins containing apoBIOO and apoE and/or via impairing the attachment or ingress routes such as the LDL-receptor which binds apoBIOO.
  • 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof is employed to treat chronic HCV infection.
  • Chronic HCV infection treatment can include, but is not limited to: reduction of the risk of hepatitis; reduction of the risk of liver fibrosis; reduction of the risk of liver cirrhosis, and reduction of the risk of hepatocellular carcinoma.
  • the compound or a salt thereof may be useful in treating non-alcoholic fatty liver disease (steatohepatitis) or risk of the diseases set forth below by reducing liver cell damage, as evidenced by a reduction in blood alanine aminotransferase.
  • non-alcoholic fatty liver disease steatohepatitis
  • risk of the diseases set forth below by reducing liver cell damage, as evidenced by a reduction in blood alanine aminotransferase.
  • 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4- oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof is employed to treat non-alcoholic fatty liver disease.
  • Non-alcoholic fatty liver disease treatment can include, but is not limited to: (a) reduction of steatohepatitis, (b) reduction of the risk of liver fibrosis, (c) reduction of the risk of liver cirrhosis, and (d) reduction of the risk of hepatocellular carcinoma.
  • the compound or a salt thereof of the present method may be useful in treating hyperuricemia or its complications as well.
  • 5-[( ⁇ 1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof is employed to treat hyperuricemia.
  • Hyperuricemia treatment can include, but is not limited to: management of primary or secondary gout (such as, for example, acute attacks, tophi, joint destruction), management of patients with leukemia, lymphoma or malignancies receiving cancer therapy which elevates levels of blood uric acid, and management of the metabolic syndrome.
  • the present invention is the use of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4- oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof in treatment of a disease or condition selected from the group consisting of an abnormality of blood lipids, atherosclerotic
  • cardiovascular disease non-alcoholic fatty liver disease (steatohepatitis), chronic hepatitis C virus infection, and hyperuricemia.
  • non-alcoholic fatty liver disease steatohepatitis
  • chronic hepatitis C virus infection hepatitis C virus infection
  • hyperuricemia hyperuricemia
  • the present invention is the use of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol- 5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof in a medicament, in therapy, and/or in the manufacture of a medicament for treatment of diseases or conditions selected from the group consisting of an abnormality of blood lipids, atherosclerotic cardiovascular disease, non-alcoholic fatty liver disease (steatohepatitis), chronic hepatitis C virus infection, and
  • the present invention is the use of the compound or
  • the disease or condition is an abnormality of blood lipids selected from the group consisting of high total cholesterol concentration, high LDL cholesterol concentration, high non- HDL cholesterol concentration, high total cholesterol/HDL cholesterol ratio, high LDL cholesterol/HDL cholesterol ratio, low HDL cholesterol concentration, high fasting triglyceride concentration, high prandial triglyceride concentration, high apoB or apoBIOO concentration, high apoE concentration, high apoB/apoB100:apoA1 ratio.
  • blood lipids selected from the group consisting of high total cholesterol concentration, high LDL cholesterol concentration, high non- HDL cholesterol concentration, high total cholesterol/HDL cholesterol ratio, high LDL cholesterol/HDL cholesterol ratio, low HDL cholesterol concentration, high fasting triglyceride concentration, high prandial triglyceride concentration, high apoB or apoBIOO concentration, high apoE concentration, high apoB/apoB100:apoA1 ratio.
  • 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol- 5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine or a pharmaceutically acceptable salt thereof is employed to treat abnormalities of blood lipids including, but are not limited to:
  • a reduction of total cholesterol, LDL cholesterol and/or non-HDL cholesterol
  • b reduction of IDL, LDL, VLDL and/or chylomicron particle number
  • c reduction of fasting triglycerides and/or prandial triglycerides, for example, to reduce the risk of pancreatitis
  • CAD Coronary artery disease
  • HCV Hepatitis C virus
  • HbA1c Hemoglobin A1c
  • EDTA Ethylene diamine tetra-acetic acid (a chelator used to prevent blood
  • NUNC tube a commercial sample tube used for cold storage
  • Apolipoprotein A1 (or Apo A1) A protein associated predominantly with high density lipoprotein.
  • Apolipoprotein B A protein associated with triglyceride containing lipoproteins. This exists in two forms, apolipoprotein B100 (which is synthesized by the liver and is the predominant circulating form in human blood) and apolipoprotein B48 (which is synthesized by the gastrointestinal tract).
  • Apolipoprotein B100 A protein associated predominantly with very low density, low density, and intermediate density lipoproteins.
  • Apolipoprotein E A protein associated with triglyceride containing lipoproteins.
  • FPG Fasting plasma glucose
  • IDL Intermediate density lipoprotein
  • LDL Low density lipoprotein
  • VLDL Very low density lipoprotein
  • HDL High density lipoprotein
  • Triglycerides triacylglyerols
  • Study 1 Otherwise healthy, type 2 diabetic subjects on monotherapy anti-diabetic therapy were enrolled in a clinical study to evaluate the effects of repeat doses of 5-[( ⁇ 1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine compared to repeat doses of sitagliptin or placebo.
  • Subjects were male or female of non-childbearing potential, 18 - 60 years of age with a fasting plasma glucose (FPG) level ⁇ 220mg per deciliter at the Screening visit and a FPG level ⁇ 250mg per deciliter on Day -2 or Day -1 before dosing, and an HbA1c between 7 and 11%, inclusive, at the Screening visit.
  • FPG fasting plasma glucose
  • Other inclusion criteria included body mass index within the range 21.8-35.2 kg/m 2 , inclusive, fasting triglycerides ⁇ 450mg per deciliter and no clinically significant thyroid or renal dysfunction at the Screening visit. Only non-smokers and subjects who did not drink an excessive amount of alcohol were allowed in the study.
  • Subjects who successfully fulfilled the study entry criteria and provided informed consent were washed off their anti-diabetic medications (metformin in most cases) and lipid-lowering medications (14 days for fibrates and 7 days for statins and other lipid lowering drugs) before being randomized to a treatment arm in the clinical study.
  • Study drug was administered orally with food for 14 days and the treatment arms were:
  • Samples were taken fasting pre-breakfast and then pre-morning dose, and then at 10, 20, 30, 60, 90, 120, 180 min after eating a standardised breakfast meal.
  • BID dosing groups For the evening meal (approximately 10h post morning dose), BID dosing groups followed the sequence of sampling, food and dosing as for breakfast, and then samples were obtained 0.5, 1 , 1.5, 2 and 3 hours post dinner.
  • the 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine QD dosing group had samples taken just before the evening meal and then 0.5, 1 , 1.5, 2 and 3 hours post dinner.
  • the evacuated blood collection tube was gently inverted 8-10 times to mix the EDTA anticoagulant with the whole blood, and the sample was placed on ice or in a refrigerator.
  • plasma was separated by refrigerated (4° C) centrifugation at 1 ,500 to 2,000 x g for a minimum of 10 minutes.
  • the resulting plasma was transferred into one 1.8 mL NUNC tube and immediately frozen in the upright position in a non-self-defrosting freezer at least at -70° C or below.
  • the samples were shipped to analytical laboratories for assay.
  • type 2 diabetic subjects on a stable dose of metformin antidiabetic therapy were enrolled in a clinical study to evaluate the effects of repeat doses of 5-[( ⁇ 1 -[3-(1 -methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine compared to repeat doses of sitagliptin or placebo.
  • Subjects were male or female of non-childbearing potential, 18 - 65 years of age with a fasting plasma glucose (FPG) level ⁇ 220mg per deciliter at the Screening visit and a FPG level ⁇ 250mg per deciliter on Day -2 or Day -1 before dosing, and an HbA1c between 6.5 and 11 %, inclusive, at the Screening visit.
  • FPG fasting plasma glucose
  • Other inclusion criteria included body mass index within the range 21.8-37.5 kg/m 2 , inclusive, fasting triglycerides ⁇ 450mg per deciliter and no clinically significant thyroid or renal dysfunction at the Screening visit. Only non-smokers and subjects who did not drink an excessive amount of alcohol were allowed in the study.
  • Samples were taken fasting pre-breakfast and then at 0.5, 1 , 1.5, 2 and 3 hours post dose.
  • BID dosing groups For the evening meal (approximately 0h post morning dose), BID dosing groups followed the sequence of sampling, food and then dosing, and then further samples were obtained 0.5, 1 , 1.5, 2 and 3 hours post dinner.
  • the 5- [( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine QD dosing group had samples taken just before the evening meal and then 0.5, 1 , 1.5, 2 and 3 hours post dinner.
  • the evacuated blood collection tube was gently inverted 8-10 times to mix the EDTA anticoagulant with the whole blood, and the sample was placed on ice or in a refrigerator.
  • plasma was separated by refrigerated (4° C) centrifugation at 1 ,500 to 2,000 x g for a minimum of 10 minutes.
  • the resulting plasma was transferred into one 1.8 mL NUNC tube and immediately frozen in the upright position in a non-self-defrosting freezer at least at -70° C or below.
  • the samples were shipped to analytical laboratories for assay.
  • Non-HDL cholesterol total cholesterol minus HDL cholesterol.
  • Apo A1 and Apo B were analyzed using their routine two point nephelometric procedure. According to the information provided by Quest Diagnostics, when either Apo A1 or Apo B in a patient's serum reacted with a specific antiserum directed against apo A1 or B, it formed insoluble complexes. Infrared light was passed through the resultant suspension and was scattered in all directions. Some of the light was scattered in a forward direction and focused onto a detector by an optical lens system. The amount of light scattered and detected was proportional to the number of insoluble complexes formed.
  • triglyceride profiles were measured using the BioAssay Systems EnzyChromTM Triglyceride Assay (Catalogue # ETGA-200) following the instructions provided by the manufacturer.
  • This assay used a single working reagent that combined triglyceride hydrolysis and glycerol measurement in one step, in which a dye reagent was oxidized to form a colored product. The increase in absorbance at 570nm was directly proportional to the concentration of triglyceride in the sample.
  • Ninety-six (96) well assay plates were read on a Genesis Synergy2 Plate Reader. Quantification of triglyceride concentration was achieved by comparing the signal from unknown samples with values obtained from a set of calibrators of known triglyceride concentration.
  • Apo E was measured using the Mabtech ELISA kit for human plasma (catalogue # 3712-1 H-20) following the instructions provided by the manufacturer. This sandwich immunoassay was specific for Apo E.
  • ELISATM plate wells were precoated by the manufacturer with an anti- apolipoprotein E mouse monoclonal antibody (E276). Diluted human plasma samples were added to the wells and incubated with shaking for approximately 2 hours. After washing with assay buffer, the
  • biotinylated monoclonal detection antibody E887-biotin
  • E887-biotin biotinylated monoclonal detection antibody
  • Non-HDL cholesterol total cholesterol minus HDL cholesterol.
  • Apo A1 and Apo B were analyzed using their routine two point nephelometric procedure. When either Apo A1 or Apo B in a patient's serum reacted with a specific antiserum directed against apo A1 or B, it formed insoluble complexes. Infrared light was passed through the resultant suspension and was scattered in all directions. Some of the light was scattered in a forward direction and focused onto a detector by an optical lens system. The amount of light scattered and detected was proportional to the number of insoluble complexes formed.
  • Non-HDL cholesterol total cholesterol minus HDL cholesterol.
  • triglyceride profiles were measured using the BioAssay Systems EnzyChromTM Triglyceride Assay (Catalogue # ETGA-200) following the instructions provided by the manufacturer.
  • This assay used a single working reagent that combined triglyceride hydrolysis and glycerol measurement in one step, in which a dye reagent was oxidized to form a colored product. The increase in absorbance at 570nm was directly proportional to the concentration of triglyceride in the sample.
  • Ninety-six (96) well assay plates were read on a Genesis Synergy2 Plate Reader. Quantification of triglyceride concentration was achieved by comparing the signal from unknown samples with values obtained from a set of calibrators of known triglyceride concentration.
  • Optical density at 450nm was measured with a reference measurement at 590nm using a Genesis Synergy2 Plate Reader. Quantification of Apo B100 concentration was achieved by comparing the signal from unknown samples with values obtained from a set of calibrators of known Apo B100 concentration.
  • Apo A1 was measured using the Mabtech ELISA kit for human plasma (catalogue # 3710-1 HP-10) following the instructions provided by the manufacturer. This sandwich immunoassay was specific for Apo A1.
  • ELISATM plate wells were precoated by the manufacturer with an anti- apolipoprotein A1 mouse monoclonal antibody (HDL110). Diluted human plasma samples were added to the wells and incubated with shaking for approximately 2 hours. After washing with assay buffer, the biotinylated monoclonal detection antibody (HDL 44) was added and incubated for approximately 1 hour. A color reaction was developed using streptavidin-horse radish peroxidase and
  • tetramethylbenzidine substrate and then stopped with H 2 SO 4 Stop Solution.
  • Optical density at 450nm was measured with a reference measurement at 590nm using a Genesis Synergy2 Plate Reader. Quantification of Apo A1 concentration was achieved by comparing the signal from unknown samples with values obtained from a set of calibrators of known Apo A1 concentration.
  • Apo E was measured using the Mabtech ELISA kit for human plasma (catalogue # 3712-1 H-20) following the instructions provided by the manufacturer. This sandwich immunoassay was specific for Apo E.
  • ELISATM plate wells were precoated by the manufacturer with an anti- apolipoprotein E mouse monoclonal antibody (E276).
  • Figure 1 shows that by 13 days of treatment there was an approximately 20 % increase from baseline of HDL cholesterol for the 150mg BID, 300mg BID and 600mg QD dose groups of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine corrected for the % change from baseline for the placebo group.
  • Figure 2 shows that by 13 days of treatment there was an approximately 20-25 % decrease from baseline of LDL cholesterol for the 300mg BID and 600mg QD dose groups of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine corrected for the % change from baseline for the placebo group.
  • Figure 3 shows that by 13 days of treatment there was an approximately 30-40 % decrease from baseline of fasting triglyceride concentration for the 150mg BID, 300mg BID and 600mg QD dose groups of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine corrected for the % change from baseline for the placebo group.
  • Sitagliptin is abbreviated as "Sit" in the Figures herein.
  • Figure 4 shows that by 13 days of treatment there was an approximately 12 % decrease from baseline of fasting Apo B concentration for the 150mg BID dose group and approximately 20% decrease for the 300mg BID and 600mg QD dose groups of 5- [( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine corrected for the % change from baseline for the placebo group.
  • Figure 5 shows that by 13 days of treatment there was an approximately 25% decrease from baseline of the fasting Apo E for the 150mg BID dose group, and approximately 30% decrease for the 300mg BID and 600mg QD dose groups of 5-[( ⁇ 1- [3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine corrected for the % change from baseline for the placebo group.
  • Figure 6 shows that by 3 days of treatment there was an approximately 50-70% decrease from baseline of weight mean triglyceride concentration [AUC(0-24h)] for the 150mg BID, 300mg BID and 600mg QD dose groups of 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4- oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyrid corrected for the % change from baseline for the placebo group.
  • Figure 7 shows that by 14 days of treatment with 300mg BID of 5-[( ⁇ 1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine there is a reduction in the concentration of plasma alanine aminotransferase in 9 of 12 patients with type 2 diabetes mellitus. The mean reduction was approximately 26%, corrected for the % change from baseline for the placebo group.
  • Figure 8 shows that by 14 days of treatment with 300mg BID of 5-[( ⁇ 1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine there is a reduction in the concentration of plasma uric acid in all 12 patients with type 2 diabetes mellitus. The mean reduction was approximately 16%, corrected for the % change from baseline for the placebo group.
  • Subjects who successfully fulfilled the study entry criteria and provided informed consent were entered into Part A of the study (completed) if (i) they were subjects not on lipid-modifying therapy who had a fasting LDLc >130mg per deciliter, or (ii) they were on 80mg atorvastatin for > 4 weeks and were tolerating the drug well.
  • these subjects were administered 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4- oxadiazol-5-yl]-4-piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine 800 mg QD alone or with 80 mg atorvastatin for 14 days.
  • atorvastatin 10 mg QD for 4 weeks followed by co-dosing of atorvastatin 10 mg QD with 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine 10Omg QD (morning);
  • atorvastatin 10 mg QD for 4 weeks followed by co-dosing of atorvastatin 10 mg QD with 5-[( ⁇ 1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4- piperidinyl ⁇ methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine 800mg QD (morning);
  • Samples were taken fasting pre-breakfast and then pre-morning dose, and then at 0.5, 1 , 1.5, 2 and 3 hours after eating a standardised breakfast meal.
  • samples were collected just before the meal and at the following times after starting the meal: 0.5, 1 , 1.5, 2 and 3 hours.
  • Apo B100 was measured using the Mabtech ELISA kit for human plasma (catalogue # 3715-1 HP-10) following the instructions provided by the manufacturer. This sandwich immunoassay is specific for Apo B100 and does not recognize Apo B48.
  • ELISA plate wells were precoated by the manufacturer with an anti-apolipoprotein B mouse monoclonal antibody (LDL 20/17). Diluted human plasma samples were added to the wells and incubated with shaking for approximately 2 hours. After washing with assay buffer, the biotinylated monoclonal detection antibody (LDL 11-biotin) was added and incubated for approximately 1 hour. A color reaction was developed using streptavidin-horse radish peroxidase and
  • Apo A1 was measured using the Mabtech ELISA kit for human plasma (catalogue # 3710-1 HP-10) following the instructions provided by the manufacturer. This sandwich immunoassay is specific for Apo A1.
  • ELISATM plate wells were precoated by the manufacturer with an anti-apolipoprotein A1 mouse monoclonal antibody (HDL110). Diluted human plasma samples were added to the wells and incubated with shaking for approximately 2 hours.
  • the biotinylated monoclonal detection antibody (HDL 44) was added and incubated for
  • Apo E was measured using the Mabtech ELISA kit for human plasma (catalogue # 3712-1 H-20) following the instructions provided by the manufacturer. This sandwich immunoassay is specific for Apo E.
  • ELISATM plate wells were precoated by the manufacturer with an anti-apolipoprotein E mouse monoclonal antibody (E276). Diluted human plasma samples were added to the wells and incubated with shaking for approximately 2 hours. After washing with assay buffer, the biotinylated monoclonal detection antibody (E887-biotin) was added and incubated for approximately 1 hour. A color reaction was developed using streptavidin-horse radish peroxidase and

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Abstract

La présente invention concerne un procédé de traitement d'un patient souffrant d'une anomalie du taux de lipides sanguins ou d'une anomalie de la concentration d'alanine aminotransférase dans le sang ou d'une anomalie de la concentration d'acide urique dans le sang, qui comprend l'administration de 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine ou un sel pharmaceutiquement acceptable de celui-ci à un mammifère, particulièrement un être humain, en ayant besoin. Le procédé peut être utilisé pour traiter la dyslipidémie et peut être employé pour d'autres anomalies sanguines survenant dans des maladies ou états tels que l'athérosclérose cardiovasculaire, virus de l'hépatite C, la stéatose hépatique non alcoolique et/ou l'hyperuricémie chez les patients.
PCT/US2011/037912 2010-05-28 2011-05-25 Traitement des anomalies de taux de lipides sanguins et d'autres états WO2011150067A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections
WO2021207644A1 (fr) * 2020-04-09 2021-10-14 Biovista, Inc. Compositions et méthodes de traitement d'infections virales
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

Citations (2)

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Publication number Priority date Publication date Assignee Title
US20080070892A1 (en) * 2006-09-15 2008-03-20 Harris Joel M Treating pain, diabetes, and disorders of lipid metabolism
US20100029650A1 (en) * 2006-12-06 2010-02-04 SMITH KLINE BEECHAM CORPORATION a corporation Bicyclic compounds and use as antidiabetics

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080070892A1 (en) * 2006-09-15 2008-03-20 Harris Joel M Treating pain, diabetes, and disorders of lipid metabolism
US20100029650A1 (en) * 2006-12-06 2010-02-04 SMITH KLINE BEECHAM CORPORATION a corporation Bicyclic compounds and use as antidiabetics

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207644A1 (fr) * 2020-04-09 2021-10-14 Biovista, Inc. Compositions et méthodes de traitement d'infections virales
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections
US11903916B2 (en) 2020-04-10 2024-02-20 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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