WO1998042340A9 - Molecules apparentees a la retinoide destinees au traitement du diabete sucre non-insulinodependant - Google Patents

Molecules apparentees a la retinoide destinees au traitement du diabete sucre non-insulinodependant

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Publication number
WO1998042340A9
WO1998042340A9 PCT/US1998/005591 US9805591W WO9842340A9 WO 1998042340 A9 WO1998042340 A9 WO 1998042340A9 US 9805591 W US9805591 W US 9805591W WO 9842340 A9 WO9842340 A9 WO 9842340A9
Authority
WO
WIPO (PCT)
Prior art keywords
tetrahydro
benzoic acid
tetramethyl
naphthyloxy
compound
Prior art date
Application number
PCT/US1998/005591
Other languages
English (en)
Other versions
WO1998042340A1 (fr
Filing date
Publication date
Application filed filed Critical
Priority to BR9808054-7A priority Critical patent/BR9808054A/pt
Priority to JP54585198A priority patent/JP2001521551A/ja
Priority to AU65763/98A priority patent/AU6576398A/en
Priority to KR1019997008746A priority patent/KR20010005678A/ko
Priority to CA002284192A priority patent/CA2284192A1/fr
Priority to NZ337927A priority patent/NZ337927A/xx
Priority to EP98911919A priority patent/EP1019049A1/fr
Priority to IL13203298A priority patent/IL132032A0/xx
Publication of WO1998042340A1 publication Critical patent/WO1998042340A1/fr
Publication of WO1998042340A9 publication Critical patent/WO1998042340A9/fr
Priority to NO994612A priority patent/NO994612L/no

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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, 7V. 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
  • control compounds insulin, dexmethasone, all-trans RA and 9-cis RA did not exhibit similar activity.
  • 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.

Abstract

La présente invention concerne des procédés permettant de traiter et/ou de prévenir le diabète sucré non-insulinodépendant chez des sujets souffrant de cette maladie ou présentant un risque important de la développer. Lesdits procédés font appel à des composés rétinoïdes spécifiques structurellement apparentés à l'acide rétinoïque 9-cis qui induit la différenciation des préadipocytes en adipocytes. Ces composés peuvent être administrés seuls ou en combinaison avec d'autres agents antidiabetogènes tels que les thiazolidinediones.
PCT/US1998/005591 1997-03-24 1998-03-24 Molecules apparentees a la retinoide destinees au traitement du diabete sucre non-insulinodependant WO1998042340A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BR9808054-7A BR9808054A (pt) 1997-03-24 1998-03-24 Método de tratamento e/ou prevenção de diabete melito não-dependente de insulina e composição
JP54585198A JP2001521551A (ja) 1997-03-24 1998-03-24 インスリン非依存性糖尿病の治療のためのレチノイド関連分子
AU65763/98A AU6576398A (en) 1997-03-24 1998-03-24 Retinoid related molecules for the treatment of non-insulin dependent diabetes mellitus
KR1019997008746A KR20010005678A (ko) 1997-03-24 1998-03-24 비인슐린의존성 당뇨병 치료용 레티노이드계 분자
CA002284192A CA2284192A1 (fr) 1997-03-24 1998-03-24 Molecules apparentees a la retinoide destinees au traitement du diabete sucre non-insulinodependant
NZ337927A NZ337927A (en) 1997-03-24 1998-03-24 Methods and compositions for treating and/or preventing non-insulin dependent diabetes mellitus (NIDDM) using specific retinoid compounds
EP98911919A EP1019049A1 (fr) 1997-03-24 1998-03-24 Molecules apparentees a la retinoide destinees au traitement du diabete sucre non-insulinodependant
IL13203298A IL132032A0 (en) 1997-03-24 1998-03-24 Retinoid related molecules for the treatment of non-insulin dependent diabetes mellitus
NO994612A NO994612L (no) 1997-03-24 1999-09-22 Retinoid-relaterte molekyler for behandling av ikke-insulinavhengig diabetes mellitus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3560497P 1997-03-24 1997-03-24
US60/035,604 1997-03-24

Publications (2)

Publication Number Publication Date
WO1998042340A1 WO1998042340A1 (fr) 1998-10-01
WO1998042340A9 true WO1998042340A9 (fr) 1999-03-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/005591 WO1998042340A1 (fr) 1997-03-24 1998-03-24 Molecules apparentees a la retinoide destinees au traitement du diabete sucre non-insulinodependant

Country Status (11)

Country Link
EP (1) EP1019049A1 (fr)
JP (1) JP2001521551A (fr)
KR (1) KR20010005678A (fr)
CN (1) CN1256630A (fr)
AU (1) AU6576398A (fr)
BR (1) BR9808054A (fr)
CA (1) CA2284192A1 (fr)
IL (1) IL132032A0 (fr)
NO (1) NO994612L (fr)
NZ (1) NZ337927A (fr)
WO (1) WO1998042340A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1813273A1 (fr) * 1998-11-12 2007-08-01 Smithkline Beecham Plc Composition pharmaceutique pour la libération modifiée d'un sensibilisateur d'insuline et un autre agent anti-diabète
AR023699A1 (es) * 1998-11-12 2002-09-04 Smithkline Beecham Corp Una composicion farmaceutica que comprende un estabilizador de insulina y un procedimiento para preparar una composicion farmaceutica
WO2002100396A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de la ptpase et d'un agent thiazolidinedione
EP1707195A4 (fr) * 2004-01-23 2007-06-20 Japan Science & Tech Agency Remede a base d'acide retinoique pour le diabete
CA2937107C (fr) * 2014-01-17 2020-12-22 Cornell University Methodes de traitement d'etats pathologiques apparentes a un syndrome metabolique a l'aide d'agonistes du recepteur de l'acide retinoique
US11191755B2 (en) 2014-01-17 2021-12-07 Cornell University Compositions and methods for providing cardioprotective effects

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2146197T3 (es) * 1989-03-08 2000-08-01 Univ Virginia Suplemento dietetico para diabeticos resistentes a la insulina.
FR2695317B1 (fr) * 1992-09-07 1995-03-10 Monal Lab Composition apte à stimuler la sécrétion d'insuline destinée au traitement du diabète non insulino-dépendant.
AU676227B2 (en) * 1993-01-22 1997-03-06 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Therapeutic agent for NIDDM
US5478852C1 (en) * 1993-09-15 2001-03-13 Sankyo Co Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of impaired glucose tolerance in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus
US5444086A (en) * 1994-03-31 1995-08-22 American Home Products Corporation Naphthalenylmethyl thiophenones as antihyperglycemic agents

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