Classifications

• • 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
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to the discovery that certain retinoid related compounds which are structurally related to 9-cis retinoic acid effectively induce the differentiation of preadipocytes to adipocytes. These compounds, and compositions containing, are useful for the treatment and/or prevention of non-insulin dependent diabetes mellitus (NIDDM).
• NIDDM non-insulin dependent diabetes mellitus
• NIDDM non- insulin dependent diabetes mellitus
• NIDDM is characterized by insulin resistance and abnormalities relating to insulin secretion and action. More specifically, NIDDM is characterized by hyperglycemia, the result of insulin resistance in peripheral tissue (skeletal muscle and adipose tissue), which occurs because insulin- stimulated uptake/utilization of glucose is blunted therein; and in the liver, which occurs because insulin suppression of glucose output is insufficient. These impairments in insulin action play an important role in the development of elevated fasting blood glucose and glucose intolerance.
• NIDDM treatments and prevention include diet and exercise (since NIDDM and insulin resistance strongly correlates with obesity).
• oral administration of hypoglycemic drugs to control blood glucose levels is another means of treating NIDDM.
• hypoglycemic agents include insulin and sulfonylurea-containing formations.
• these therapies suffer from significant disadvantages, in particular, the occurrence of potentially life-threatening hypoglycemia which is attributable to hyperinsulinemia. This is problematic as hypoglycemia is associated with an elevated risk of cardiovascular disease, the major killer of diabetics. Therefore, providing a method of treating diabetes that does not increase circulatory insulin concentrations would be highly beneficial.
• thiazolidinediones which drugs have been shown to increase sensitivity to insulin in patients that are resistant to this hormone.
• Thiazolidinediones reportedly ameliorate insulin-resistance and normalize plasma glucose and insulin (where elevated) without causing a hypoglycemic state, even when administered at very high dosages.
• the TZD insulin sensitizers e.g., ciglitazone, englitazone, pioglitazone, BRL 49653 (5-[(4-(2- (methyl-2-pyridinylamino)-ethoxy]phenyl]methyl]-2,4-thiazolidinedione) and troglitazone, enhance insulin-mediated suppression of hepatic glucose output and insulin-stimulated glucose uptake and utilization by adipose tissue. Also, TZDs have been reported to alter glucose transporter (e.g. Glut 4) expression which contributes to increased insulin responsiveness.
• glucose transporter e.g. Glut 4
• TZDs One specific TZD member, troglitazone, was recently reported to be effective against NIDDM in a phase III clinical trial (Nolan et al, N. Engl. J. Med., 331 : 1188-1193, 1994).
• the potency of TZDs as effective anti-diabetic agents closely matches that adipogenic action, i.e. their ability to differentiate preadipocytes into adipocytes (Harris and Kletzien, Mol. Pharmacol, 45:439- 445, 1994; Wilson et al, J. Med. Chem., 39:665-668, 1996).
• TZDs have been reported to convert myogenic cells into adipocyte-like cells (Teboul et al, J. Biol. Chem., 270:28183-28187, 1995).
• TZDs have been shown to function as regulators of the nuclear receptor PPAR ⁇ (Lehmann et al, J. Biol. Chem.,
• NIDDM NIDDM
• specific retinoids of the present invention are not mentioned therein.
• the present invention relates to the discovery that specific retinoid- related molecules, which do not exhibit typical retinoid activities, may be used as therapeutics. These compounds, unlike normal retinoids, exhibit reduced or no ability to induce the differentiation of F9 teratocarcinoma cells or P12 pluripotent teratocarcinoma cells. However, these compounds very potently potentially induce the differentiation of preadipocytes to adipocytes.
• Figure 1 compares the ability of various retinoids according to the invention to induce the differentiation of preadipocytes to adipocytes at different concentrations.
• Figure 2 compares the ability of various retinoids according to the invention to induce the differentiation of preadipocytes to adipocytes over a seven day time period.
• compositions adopted for the treatment or prevention of NIDDM that comprise the combination of at least one retinoid-related molecule structurally related to 9-cis retinoic acid, which molecule induces the differentiation of preadipocytes to adipocytes and at least one triazolidinedione (TZD) compound.
• the present invention is based on the discovery that certain retinoid- type molecules, which do not exhibit typical retinoid activities, exhibit the ability to induce differentiation of preadipocytes to adipocytes. Also, these molecules do not exhibit adverse side effects in vivo. This adipogenic action renders these compounds, and isomers or pharmaceutically acceptable salts thereof, well suited for the treatment or prevention of NIDDM. In particular, these compounds should exhibit an effective anti-diabetogenic action based on their adipogenic activity, similar to TZDs. However, unlike TZDs, these retinoid compounds should not exhibit toxic side effects upon in vivo administration because these molecules do not exhibit typical retinoid toxicities and have been shown to be well tolerated in an animals.
• these compounds effectively promote adipogenesis. Therefore, these compounds or isomers or pharmaceutically acceptable salts thereof may be used for the treatment and/or prevention of NIDDM.
• a therapeutic/prophylactic composition which comprises a therapeutically or prophylactically effective amount of at least one compound according to the invention will be administered to a subject having or at risk of developing NIDDM.
• Such pharmaceutical/therapeutic compositions will comprise a vehicle, carrier or diluent which is pharmaceutically acceptable and compatible with the mode of regime of administration selected for the given composition, and a therapeutically or prophylactically effective amount of at least one compound according to the invention, or a pharmaceutically acceptable salt or isomer thereof.
• the administration of the compounds according to the invention can be carried out by any suitable means, e.g., systemically, enterally, parenterally, topically or ocularly. However, oral administration is generally preferred.
• the medicinal/pharmaceutical compositions may be in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, elixirs, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles which permit a controlled release.
• the compositions may be in the form of solutions or suspensions for perfusion or for injection.
• the compounds according to the invention are generally administered at a daily dose of about 0.1 mg/kg to 100 mg/kg of body weight which are administered at the rate of 1 to 3 doses per diem.
• the pharmaceutically compositions based on compounds according to the invention may be provided in the form of ointments, creams, milks, pommades, powders, salves, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be provided in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels which permit for controlled release. These compositions for topical administration may, moreover, be provided either in anhydrous form or in an aqueous form. For ocular administration, they are principally eye washes.
• compositions for topical or ocular application contain at least one compound according to the invention or one of its salts, at a concentration preferably ranging from 0.001% to 5% by weight relative to the total weight of the composition.
• compositions according to the invention may, in addition, contain inert or pharmacodynamically active additives.
• the compositions according to the invention may comprise other drugs which are suitable for treating or preventing NIDDM.
• the therapeutic/prophylactic compositions of the invention will comprise at least one retinoid compound according to the invention, in combination with at least one thiazolidinedione compound such as ciglitazone, englitazone, pioglitazone, BRL 49653 (5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]2-4-thiazolidinedione, and troglitazone.
• adipogenic agents should provide at least the additive and potentially synergistic effects on adipogenic activity.
• the subject therapeutic or prophylactic compositions may further comprise other drugs useful for the treatment or prevention of diabetes.
• the retinoid compounds of the present invention as noted, will preferably be used to treat persons already diagnosed with NIDDM, i.e., who exhibit an active disease condition.
• another important application of the present invention comprises the use of the subject retinoid compounds for the prevention of NIDDM in persons who are at substantial risk of developing diabetes, e.g. because of genetic and/or other risk factors.
• risk factors include, by way of example, obesity, and pancreatic transplant.
• these compounds or pharmaceutically acceptable salts thereof may be used or for treating persons who exhibit the early, i.e., preclinical signs of NIDDM.
• Methods for identifying persons who exhibit the early signs of NIDDM or who are at substantial risk of developing NIDDM are known in the diabetic art, and include measuring glucose levels.
• 3T3-L1 preadipocyte cells were seeded at 5xl0 4 cells per well in DMEM and 10% calf serum in 24 well tissue culture plates. Two days after reaching confluence, differentiation was induced by the addition of different compounds according to the invention as well as suitable control compounds in DMEM containing 10% fetal calf serum. Media and compounds were changed every three days. Cells were fixed after 7 days post-confluency and the accumulation of lipid droplets in the cytoplasm was determined by oil red O staining. All cells, including the control cells (vehicle), were treated with the same volume of dimethyl sulfoxide (DMSO), at a level which did not exceed 0.2% final solvent concentration.
• DMSO dimethyl sulfoxide
• Oil red O staining Seven days post confluency, the cells were washed twice with PBS, fixed at 10% formalin and washed one more time with PBS. Cells were then stained with 60% Oil Red O solution for 30 minutes. Cells were then washed twice with water for 15 minutes each.
• the Oil Red O stock solution was prepared from 0.5 g Oil Red O dissolved in 100 ml isopropanol and it was filtered prior dilution in PBS to render 60% Oil Red O solution.
• 3T3-L1 preadipocyte cells were seeded at 5xl0 4 cells per well in DMEM and 10% calf serum in 24 well tissue culture plates. Two days after reaching confluence, differentiation was induced by addition of the different compounds according to the invention in DMEM containing 10% fetal calf serum (Day 0). Media and compounds were changed every three days. Cells were fixed at the indicated days and processed as explained in Example I.
• DMSO dimethyl sulfoxide
• cells were treated with 10 ⁇ g insulin per ml and 1 ⁇ M dexamethasone (Ins/Dex). 1 ⁇ M All-trans RA (tRA) and 2 ⁇ M 9-cis RA (9cRA) were used as additional controls.
• control compounds insulin, dexmethasone, all-trans RA and
• the results obtained substantiate that the compounds of the invention effectively induce adipogenesis in a time and concentration-dependent manner. Accordingly, they should provide effective therapeutic and/or prophylactic agents for treating and/or preventing NIDDM in subjects in need of such treatment.

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• 1998
  • 1998-03-24 JP JP54585198A patent/JP2001521551A/ja active Pending
  • 1998-03-24 IL IL13203298A patent/IL132032A0/xx unknown
  • 1998-03-24 BR BR9808054-7A patent/BR9808054A/pt not_active Application Discontinuation
  • 1998-03-24 KR KR1019997008746A patent/KR20010005678A/ko not_active Application Discontinuation
  • 1998-03-24 CA CA002284192A patent/CA2284192A1/en not_active Abandoned
  • 1998-03-24 AU AU65763/98A patent/AU6576398A/en not_active Abandoned
  • 1998-03-24 WO PCT/US1998/005591 patent/WO1998042340A1/en not_active Application Discontinuation
  • 1998-03-24 EP EP98911919A patent/EP1019049A1/de not_active Withdrawn
  • 1998-03-24 NZ NZ337927A patent/NZ337927A/xx unknown
  • 1998-03-24 CN CN98805131A patent/CN1256630A/zh active Pending
• 1999
  • 1999-09-22 NO NO994612A patent/NO994612L/no not_active Application Discontinuation

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