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WO2016097036A1 - Ligand du récepteur des oestrogènes destiné à être utilisé dans le traitement du mélanome - Google Patents

Ligand du récepteur des oestrogènes destiné à être utilisé dans le traitement du mélanome Download PDF

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Publication number
WO2016097036A1
WO2016097036A1 PCT/EP2015/080067 EP2015080067W WO2016097036A1 WO 2016097036 A1 WO2016097036 A1 WO 2016097036A1 EP 2015080067 W EP2015080067 W EP 2015080067W WO 2016097036 A1 WO2016097036 A1 WO 2016097036A1
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WIPO (PCT)
Prior art keywords
melanoma
compound
treatment
prophylaxis
interferon
Prior art date
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Ceased
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PCT/EP2015/080067
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English (en)
Inventor
Marina MONTAGNANI MARELLI
Roberta Manuela MORETTI
Patrizia LIMONTA
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Karo Healthcare AB
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Karo Bio AB
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Application filed by Karo Bio AB filed Critical Karo Bio AB
Publication of WO2016097036A1 publication Critical patent/WO2016097036A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of a specific estrogen receptor ligand for treating disease, specifically, for the treatment or prophylaxis of melanoma.
  • Estrogens are key signaling molecules that regulate various physiological processes such as cell growth, reproduction, development and differentiation. They also play a role in several pathological processes of hormone dependent diseases, including cancers.
  • Cellular signaling by estrogens is mediated via the estrogen receptors a and ⁇ (ERa and ERP).
  • ERa is mainly expressed in reproductive tissues (uterus, ovary), breast, kidney, bone, white adipose tissue and liver, while the highest levels of ERP expression are found in the ovary, central nervous system, cardiovascular system, lung, male reproductive organs, prostate, colon, kidney and the immune system.
  • ERa and ERP the highest levels of ERP expression are found in the ovary, central nervous system, cardiovascular system, lung, male reproductive organs, prostate, colon, kidney and the immune system.
  • ER receptor agonists and/or antagonists for the treatment of a very wide range of diseases.
  • Very many synthetic compounds that are active at estrogen receptors are known. For example
  • WO2006/019831 discloses such compounds.
  • WO2008/043567 discloses such compounds.
  • WO2009/121910 discloses such compounds.
  • WO2009/012954 discloses such compounds.
  • WO2009/124968 discloses such compounds.
  • WO2009/127686 discloses such compounds.
  • WO2010/031852 discloses such compounds.
  • WO2011/042473 discloses such compounds.
  • WO2009/127686 discloses compounds which may be used in the treatment of bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive
  • WO2011/042473 and WO2011/042475 disclose compounds which may be used in the treatment of bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flushes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, perimenopausal depression, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, anger management, hearing disorders, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer,
  • This invention provides a method for the treatment or prophylaxis of melanoma in a subject, which comprises administering to the subject a therapeutically effective amount of a compound having the formula:
  • the invention further provides a compound of the formula (I) or a salt or an ester thereof for use in the treatment or prophylaxis of melanoma.
  • the invention further provides a compound of the formula (I) or a salt or an ester thereof for use in the manufacture of a medicament for the treatment or prophylaxis of melanoma.
  • the present invention finds utility in the treatment or prophylaxis of melanoma by administering to a subject, particularly to a mammal, especially a human, a therapeutically effective amount of the compound (Z)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4-hydroxyphenyl)-lH-indole-3- carboximidamide (hereinafter "Com ound I”):
  • Compound I is known from WO 2009/127686, in which it is Example 11. It has now been shown to be surprisingly active against melanoma cells.
  • Salts of Compound I which are suitable for use in medicine are those wherein a counterion is pharmaceutically acceptable.
  • Suitable salts include those formed with organic or inorganic acids or bases.
  • suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C r C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxalic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D- glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl- propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.
  • Particular salts of Compound I include acid addition salts such as those formed from
  • hydrochloric hydrobromic, acetic, p-toluenesulfonic, tartaric, sulphuric, succinic, phosphoric, oxalic, nitric, methanesulfonic, malic, maleic and citric acid.
  • Compound I may have an appropriate group converted to an ester.
  • ester groups formed from an -OH group include -O.CO.R B and -O.S0 2 R B , where R B is preferably independently selected from the group consisting of hydrogen and Ci-4alkyl.
  • R B is preferably independently selected from the group consisting of hydrogen and Ci-4alkyl.
  • An ester or salt may contain one or more chiral (asymmetric) centers. All individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.
  • a compound which, upon administration to the recipient, is capable of being converted into Compound I as described above, or an active metabolite or residue thereof, is known as a "prodrug".
  • a prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.
  • the amount of active ingredient which is required to achieve a therapeutic effect will vary with the particular route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, as well as the severity of the melanoma.
  • An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • the subject may be a mammal, especially a human.
  • Oral dosages for use in the present invention will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day, for adult humans.
  • the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient.
  • the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • the compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the compounds can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • compositions useful according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered does pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
  • parenteral including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular
  • inhalation including fine particle dusts or mists which may be generated by means of various types of metered does pressurized aerosols
  • nebulizers or insufflators rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
  • sterile liquid carrier for example saline or water-for-injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3- butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3- butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia.
  • exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • compounds useful in the invention may be used as the sole active ingredient in a medicament, it is also possible for the compounds to be used in combination with one or more further active agents, and the use of such combinations provides one preferred embodiment of the invention.
  • Such further active agents may be agents useful in the treatment or prophylaxis of melanoma, or other pharmaceutically active materials, but are preferably agents known for the treatment or prophylaxis of melanoma. Such agents are known in the art.
  • further active agents known in the treatment or prophylaxis of melanoma include interferon a-2b;
  • the invention also provides a method for the treatment or prophylaxis of melanoma in a subject, which comprises administering to the subject a therapeutically effective amound of Compound I or a salt or ester thereof, together with one or more compounds known for the treatment or prophylaxis of melanoma, for example one or more of interferon a-2b; PEGylated interferon a-2b; interleukin-2; dacarbazine (DTIC);
  • temozolomide fotemustine; thalidomide; GM-CSF; cisplatin; carmustine; vinblastine;
  • oblimersen aldesleukin; dabrafenib; ipilimumab; pembrolizumab; trametinib; vemurafenib nivolumab; cobimetinib; and talimogene laherparepvec (for example one or more of interferon a- 2b; PEGylated interferon a-2b; interleukin-2; dacarbazine (DTIC); temozolomide; fotemustine; thalidomide; GM-CSF; cisplatin; carmustine; vinblastine; oblimersen; aldesleukin; dabrafenib; ipilimumab; pembrolizumab; trametinib; and vemurafenib).
  • interferon a- 2b PEGylated interferon a-2b; interleukin-2; dacarbazine (DTIC); temozo
  • the invention further provides Compound I or a salt or ester thereof for use in the treatment or prophylaxis of melanoma, together with one or more compounds known for the treatment or prophylaxis of melanoma, for example one or more of interferon a-2b; PEGylated interferon a-2b; interleukin-2; dacarbazine (DTIC); temozolomide; fotemustine; thalidomide; GM-CSF; cisplatin; carmustine; vinblastine; oblimersen; aldesleukin; dabrafenib; ipilimumab; pembrolizumab; trametinib; vemurafenib; nivolumab; cobimetinib; and talimogene laherparepvec (for example one or more of interferon a- 2b; PEGylated interferon a-2b; interleukin-2; dacarb
  • interferon a-2b interferon a-2b
  • PEGylated interferon a-2b interleukin-2
  • dacarbazine DTIC
  • temozolomide fotemustine; thalidomide; GM-CSF; cisplatin; carmustine; vinblastine; oblimersen; aldesleukin; dabrafenib; ipilimumab; pembrolizumab; trametinib; vemurafenib; nivolumab; cobimetinib; and talimogene laherparepvec (for example one or more of interferon a-2b; PEGylated interferon a- 2b; interleukin-2; dacarbazine (DTIC); temozolomide; fotemustine; thalidomide; GM-CSF; cisplatin; carmustine
  • compositions comprising the compound of the formula I or a salt or ester thereof together with one or more compounds known for the treatment or prophylaxis of melanoma, for example one or more of interferon a-2b; PEGylated interferon a-2b; interleukin-2; dacarbazine (DTIC); temozolomide; fotemustine; thalidomide; GM-CSF; cisplatin; carmustine; vinblastine; oblimersen; aldesleukin; dabrafenib; ipilimumab; pembrolizumab; trametinib; vemurafenib; nivolumab; cobimetinib; and talimogene laherparepvec (for example one or more of interferon a- 2b; PEGylated interferon a-2b;
  • the precise dosage of the other pharmaceutically active material will vary with the dosing schedule, the oral potency of the particular agent chosen, the age, size, sex and condition of the subject (typically mammal or human), the nature and severity of the melanoma, and other relevant medical and physical factors.
  • a precise pharmaceutically effective amount cannot be specified in advance and can be readily determined by the caregiver or clinician.
  • An appropriate amount can be determined by routine experimentation from animal models and human clinical studies. For humans, an effective dose will be known or otherwise able to be determined by one of ordinary skill in the art.
  • melanoma There are four basic categories of melanoma: superficial spreading melanoma, lentigo melanoma, acral lentiginous melanoma and nodular melanoma.
  • the present invention is applicable to any of these four categories. Examples
  • the human BLM melanoma cell line used in the experiments was donated by Dr. G.N. van Muijen (Department of Pathology, Radbound University Nijmegen Medical Center, Nijmegen, The Netherlands).
  • the BLM cells were cultured in DMEM medium supplemented with 10% FBS, glutamine and antibiotics, in humidified atmosphere of 5% C0 2 /95% air at 37 °C. All experiments were performed at passages ⁇ 25-30.
  • 17 -Estradiol was purchased from Sigma- Aldrich (Milan, Italy).
  • Diarylpropionitrile (DPN) was purchased from Tocris Biosciences (Bristol, UK).
  • BLM melanoma cells were plated (15xl0 3 cells/dish) in 6-cm dishes in DMEM complete medium. After 48 h, the medium was replaced with phenol red free medium supplemented with 10% charcoal stripped FBS. The various test compounds were then added at a final concentration of 10 "8 M at intervals of 48 h. DMSO was present in the proliferation assay medium for the different compounds and the control at a final dilution of 1 : 1000,000. After six days of treatments, cells were harvested and counted by hemocytometer. Results
  • Comparative compounds 1 and 2 are known from WO 2011/042473 to be active in the treatment of melanoma.
  • compound I according to the invention which is not known to be active in the treatment of melanoma, proved to be more active against melanoma cells than either of these comparative compounds.
  • Compound I was also more active than the naturally- occurring ERP agonist 17P-estradiol.
  • the compound DPN was also included in this testing. This compound is known to be a highly active and selective ERP agonist, but it is not believed to be known for the treatment of melanoma.
  • DPN is not, however, a serious candidate for the treatment of melanoma because of its lack of bioavailability when administered by the oral route.
  • the compound I of the present invention is however believed to be capable of oral administration. In addition, it demonstrates good metabolic stability.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement ou de prophylaxie du mélanome chez un sujet, qui consiste à administrer au sujet une quantité thérapeutiquement efficace d'un composé ayant la formule (I) : ou un sel ou un ester de celui-ci. L'invention concerne également un composé ayant la formule, ou un sel ou un ester de celui-ci, destiné à être utilisé dans le traitement ou la prophylaxie du mélanome; l'utilisation d'un composé ayant la formule (I), ou un sel ou un ester de celui-ci, dans la fabrication d'un médicament destiné au traitement ou à la prophylaxie du mélanome; et une composition comprenant un composé ayant la formule (I), ou un sel ou un ester de celui-ci, conjointement avec un ou plusieurs composés additionnels connus pour le traitement ou la prophylaxie du mélanome.
PCT/EP2015/080067 2014-12-17 2015-12-16 Ligand du récepteur des oestrogènes destiné à être utilisé dans le traitement du mélanome Ceased WO2016097036A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1422448.9 2014-12-17
GB201422448 2014-12-17

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WO2016097036A1 true WO2016097036A1 (fr) 2016-06-23

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PCT/EP2015/080067 Ceased WO2016097036A1 (fr) 2014-12-17 2015-12-16 Ligand du récepteur des oestrogènes destiné à être utilisé dans le traitement du mélanome

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009127686A1 (fr) * 2008-04-16 2009-10-22 Karo Bio Ab Nouveaux ligands du récepteur d’œstrogène
WO2011042475A1 (fr) * 2009-10-07 2011-04-14 Karo Bio Ab Pyrazoles substitués en tant que ligands du récepteur d'estrogène
WO2011042473A2 (fr) * 2009-10-07 2011-04-14 Karo Bio Ab Nouveaux ligands des récepteurs des œstrogènes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009127686A1 (fr) * 2008-04-16 2009-10-22 Karo Bio Ab Nouveaux ligands du récepteur d’œstrogène
WO2011042475A1 (fr) * 2009-10-07 2011-04-14 Karo Bio Ab Pyrazoles substitués en tant que ligands du récepteur d'estrogène
WO2011042473A2 (fr) * 2009-10-07 2011-04-14 Karo Bio Ab Nouveaux ligands des récepteurs des œstrogènes

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Title
DE GIORGI V ET AL: "Oestrogen receptor beta and melanoma: a comparative study", BRITISH JOURNAL OF DERMATOLOGY, vol. 168, no. 3, March 2013 (2013-03-01), pages 513 - 519, XP002754748 *
MARZAGALLI, M. ET AL.: "Dissecting the role of ERbeta in melanoma growth and its cross-talk with the tumor epigenome", 28 September 2013 (2013-09-28), pages 1 - 8,40, XP002754749, Retrieved from the Internet <URL:http://aibg2013.azuleon.org/_docs/AIBG2013_Programme&Abstracts.pdf> [retrieved on 20160224] *
PATERNI ILARIA ET AL: "Estrogen receptors alpha (ER[alpha]) and beta (ER[beta]): Subtype-selective ligands and clinical p", STEROIDS, vol. 90, 24 June 2014 (2014-06-24), ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, pages 13 - 29, XP029048268, ISSN: 0039-128X, DOI: 10.1016/J.STEROIDS.2014.06.012 *
SCHMIDT ADRIANA N ET AL: "Oestrogen receptor-beta expression in melanocytic lesions.", EXPERIMENTAL DERMATOLOGY, vol. 15, no. 12, December 2006 (2006-12-01), pages 971 - 980, XP002754747, ISSN: 0906-6705 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death

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