WO2011117453A1 - Utilisation de composés à structure 2-cyclopenténone pour l'inhibition d'enzymes de la famille des aldo-céto réductases - Google Patents

Utilisation de composés à structure 2-cyclopenténone pour l'inhibition d'enzymes de la famille des aldo-céto réductases Download PDF

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WO2011117453A1
WO2011117453A1 PCT/ES2011/070201 ES2011070201W WO2011117453A1 WO 2011117453 A1 WO2011117453 A1 WO 2011117453A1 ES 2011070201 W ES2011070201 W ES 2011070201W WO 2011117453 A1 WO2011117453 A1 WO 2011117453A1
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Prior art keywords
compounds
aldo
akr1
enzymes
inhibition
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PCT/ES2011/070201
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English (en)
Spanish (es)
Inventor
María Dolores PÉREZ-SALA GOZALO
Beatriz DÍEZ DACAL
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Consejo Superior De Investigaciones Científicas (Csic)
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Publication of WO2011117453A1 publication Critical patent/WO2011117453A1/fr

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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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha

Definitions

  • Aldo-keto reductases constitute a super-ammonium of enzymes that catalyze the oxidoreduction of a wide variety of substrates dependent on NAD (P) (H).
  • P NAD
  • aldose reductase (AKR1 B1) catalyzes the conversion of glucose to sorbitol and it has been shown that said enzyme plays a crucial role in the inflammatory response, probably through its ability to generate lipid aldehydes with effect proinflammatory [Ramana et al., Circulation 2006, 1 14, 1838-46].
  • AKR1 B1 also has very important implications in the development of diabetic complications.
  • AKR1 B10 Other enzymes in this family, such as AKR1 B10, have implications for the development of tumors or their resistance to anticancer agents. It has been found that the expression of AKR1 B10 is elevated in certain types of tumors, which is why it is currently considered a tumor marker. It has also been shown that the inhibition of AKR1 B10 or the reduction of its expression has an antitumor effect in cellular models [Yan et al., Int. J. Cancer, 2007, 121, 2301-6], so that the search for inhibitors of this enzyme is an active field of investigation.
  • AKR1 B1 The range of enzyme inhibitor compounds of the aldoketo reductases family that have been described over time is very wide.
  • AKR1 B1 the available inhibitors of AKR1 B1 are sorbinil, tolrestat and zopolrestat. IC 50 concentrations of these inhibitors are in the micromolar range.
  • sorbinil and tolrestat have IC50 of 3.6 ⁇ and 0.4 ⁇ , respectively.
  • IC50 of 8 ⁇ for Zopolrestat and 100 ⁇ for sorbinil have been described.
  • Epalrestat The compound known as Epalrestat has been used in clinical trials in Japan, apparently with good results in some patient groups. For example, a protective effect against the development of diabetic retinopathy has been documented, although it did not produce improvement once established. It has also shown positive effects in some studies in diabetic neuropathy. It has been proposed that the Ranirestat compound may also have clinical utility in the future, however the available evidence is inconclusive and there is still some controversy regarding the possible use of clinically available inhibitors.
  • the present invention relates to the use of compounds containing cyclopentenone structure to inhibit the activity of enzymes of the aldose reductases family both in vitro and in cells or organisms.
  • the present invention relates to a compound of formula (I)
  • R and R2 are independently substituted or unsubstituted alkyl or alkenyl groups with a carbon number between 1 and 10,
  • R 3 is selected from hydrogen or -OH
  • alkyl refers, in the present invention, to radicals of hydrocarbon chains, linear or branched, having 1 to 10 carbon atoms, preferably 5 to 7, and which are attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, tere-butyl, sec-butyl, n-pentyl, n-hexyl, etc.
  • the alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxy, alkoxy, carboxyl, carbonyl, cyano, acyl, alkoxycarbonyl, amine, nitro, mercapto and alkylthio.
  • alkenyl refers to hydrocarbon chain radicals containing one or more double carbon-carbon bonds, for example, vinyl, 1-propenyl, allyl, isoprenyl, 2-butenyl, 1, 3-butadienyl etc.
  • the radicals Alkenyls may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • the active structure of the compounds with cyclopentenone structure is an ⁇ , ⁇ -unsaturated carbonyl that determines the presence of electrophilic carbons capable of undergoing attacks by nucleophilic groups such as thiols in proteins and giving rise to covalent adducts known as adducts. from Michael.
  • the compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers.
  • the individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof.
  • the individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • the compounds of the invention may be in crystalline form as free compounds or as solvates.
  • solvate includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.
  • the nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate.
  • Solvates can be obtained by conventional methods of solvation known by the subject matter experts.
  • the compounds of formula (I), their salts or solvates will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts or solvates.
  • the compound with cyclopentenone structure is a prostaglandin of the PGA1 type, or some of its isomers or derivatives.
  • the present invention relates to the use of a compound of formula (I) is selected from the following group:
  • the compounds of formula (I) described can be used as inhibitors of aldo-keto reductases in diseases and pathological conditions in which these enzymes are overexpressed, such as inflammatory processes, neuropathies, nephropathies and diabetic retinopathies, tumors or resistance from tumors to treatment with anticancer agents.
  • a preferred embodiment of the present invention is the use of compounds of formula (I) in the manufacture of a medicament for combating diabetic complications.
  • Another preferred embodiment of this invention is the use of compounds of formula (i) to inhibit aldose reductase in tumor processes in which this enzyme is overexpressed, in addition to being used as therapy. adjuvant to anticancer treatment together with a chemotherapeutic agent.
  • the compounds described herein interact with enzymes at a different site than most of the available inhibitors, the compounds of formula (I) can be used in the preparation of mixed inhibitors that combine various types of structures to increase potency or the specificity of the inhibition.
  • Figure 2 Shows the inhibition of AKR1 B1 by various compounds in vitro.
  • Figure 3 Shows the inhibition of AKR1 B10 in COS7 cells.
  • A COS7 cells transfected with an AKR1 B10 expression plasmid
  • B COS7 cells transfected with "empty" expression plasmids or with the cDNAs of wild or mutated AKR1 B10 in cysteine 298.
  • Example 1 inhibition of ia AKR1 B1 ⁇ n Vitro.
  • the recombinant AKR1 B1 obtained from the Wako Chemicals, USA, was incubated at a concentration of 5 ⁇ in 0.5 mM sodium phosphate, pH 7.0 with 100 ⁇ DTT and 1% glycerol, in the presence of vehicle (DMSO ) or PGA1 at the concentrations indicated for 2 h at room temperature in 100 ⁇ of final volume. The incubation mixture was then diluted with 900 ⁇ of assay buffer and the enzymatic activity was determined as described below ( Figure 1).
  • AKR1 B1 The recombinant AKR1 B1 was incubated, as described above, in the presence of vehicle or of the indicated compounds at a concentration of 50 ⁇ , except fenofibrate and cyclopentenone (CP) which were used at 100 ⁇ , and 15-deoxy-PGJ2 (15d -PGJ2) which was used at 10 ⁇ , for 2 h at room temperature and then the enzymatic activity was determined (Figure 2).
  • CP fenofibrate and cyclopentenone
  • 15d -PGJ2 15-deoxy-PGJ2
  • Example 2 Inhibition of the aidosa keto reductase (AKR1 B10) expressed in COS-7 cells by compounds with cyclopentenone structure of the type of ia PGA1.
  • COS7 cells are cultured in DMEM medium with 10% (v / v) fetal serum and streptomycin penicillin antibiotics.
  • the expression plasmid of the AKR1 B10 was obtained from the Origene trading house.
  • the ORF of the AKR1 B10 obtained from this plasmid has been cloned into the plasmid pECFL-KZ-AU5.
  • the resulting construction pECFL-KZ-AU5- AKR1 B10 is an expression vector for mammalian cells of the enzyme AKR1 B10 with an AU5 epitope at its N-terminal end. This vector or the empty vector has been transfected into COS7 cells using the Lipofectamine 2000 reagent following the manufacturer's instructions (Invitrogen).
  • the transfected cells After 24 hours the transfected cells have been incubated in the presence of the compounds with cyclopentenone PGA1 or biotinylated structure (PGA1-B) at 60 ⁇ or with vehicle only (DMSO). After 24 hours of treatment the cells have been lysed and the cytosolic fractions (S100) have been obtained by ultracentrifugation at 200,000xg for 30 min.
  • PGA1-B biotinylated structure
  • DMSO vehicle only
  • the aldose reductase activity present in these fractions has been determined by a colorimetric assay using D, L-glyceraldehyde as a substrate.
  • the reagent concentrations in the assay have been: 100 mM Sodium Phosphate Buffer pH 6.8, 200 ⁇ NADPH, 10 mM D, L-glyceraldehyde, 50 pg total protein (cytosolic fraction).
  • PGA1 induces a decrease in aldose reductase activity in these cells of approximately 50% for a 60 ⁇ concentration of the compound ( Figure 3).
  • the compound with cyclopentenone structure PGA1 -B which consists of a molecule of PGA1 to which a biotin molecule has been linked by a spacer, shows an inhibitory effect similar to that of PGA1 ( Figure 3).
  • Example 3 Inhibition of aldose keto-reductase activity in lung carcinoma cells A549 A549 lung carcinoma cells (ref ATCC) are grown in RPMI medium with 10% (v / v) fetal serum and antibiotics gentamicin and penicillin / streptomycin.
  • cytosolic cell fractions S100 were obtained as detailed in Example 1 and the aldose reductase activity present was determined by the spectrophotometric assay described above.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation d'une série de composés possédant un noyau de 2-cyclopenténone substitué par des chaînes alkyliques et alkényliques qui s'avèrent être des inhibiteurs d'enzymes aldo-céto réductases (AKR), plus particulièrement de la AKR1 B1 et AKR1 B10. Les composés de la présente invention sont également utiles pour le traitement de maladies et états pathologiques dans lesquels lesdites enzymes sont impliquées.
PCT/ES2011/070201 2010-03-25 2011-03-25 Utilisation de composés à structure 2-cyclopenténone pour l'inhibition d'enzymes de la famille des aldo-céto réductases WO2011117453A1 (fr)

Applications Claiming Priority (2)

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ESP201030449 2010-03-25
ES201030449A ES2365587B1 (es) 2010-03-25 2010-03-25 Uso de compuestos con estructura 2-ciclopentenona para la inhibición de enzimas de la familia de las aldo-keto reductasas.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017079402A1 (fr) * 2015-11-04 2017-05-11 Beijing Normal University Hong Kong Baptist University United International College Substrats de akr1b1/akr1b10 comme médicaments anti-cancéreux

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FRANZESE, O. ET AL.: "Effect of prostaglandin Al on proliferation and telomerase activity of human melanoma cells in vitro", MELANOMA RESEARCH, vol. 8, 1998, pages 323 - 328 *
GAYARRE, J. ET AL.: "Modification of proteins by cyclopentenone prostaglandins is differentially modulated by GSH in vitro", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 1096, 2007, pages 78 - 85 *
ROSSI, A. ET AL.: "Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IKB kinase", NATURE, vol. 403, no. 6765, 2000, pages 103 - 108 *
STRAUS, D.S. ET AL.: "Cyclopentenone prostaglandins: new insights on biological activities and cellular targets", MEDICINAL RESEARCH REVIEWS, vol. 21, no. 3, 2001, pages 185 - 210 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017079402A1 (fr) * 2015-11-04 2017-05-11 Beijing Normal University Hong Kong Baptist University United International College Substrats de akr1b1/akr1b10 comme médicaments anti-cancéreux
US11524017B2 (en) 2015-11-04 2022-12-13 Beijing Normal University Hong Kong Baptist University United International College Method of using substrates of AKR1B1/AKR1B10 as anti-cancer drugs

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ES2365587A1 (es) 2011-10-07

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