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WO2016030445A1 - Aminoguanidines de formule (i) à utiliser dans le traitement de la fibrose - Google Patents

Aminoguanidines de formule (i) à utiliser dans le traitement de la fibrose Download PDF

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Publication number
WO2016030445A1
WO2016030445A1 PCT/EP2015/069603 EP2015069603W WO2016030445A1 WO 2016030445 A1 WO2016030445 A1 WO 2016030445A1 EP 2015069603 W EP2015069603 W EP 2015069603W WO 2016030445 A1 WO2016030445 A1 WO 2016030445A1
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Prior art keywords
compound
fibrosis
guanidine
chloro
carbon atoms
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Inventor
Maria Kristina Gunilla EKSTRÖM
Sara Christina WENGLÉN
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Anamar AB
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Anamar AB
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Priority claimed from GB201415331A external-priority patent/GB201415331D0/en
Priority claimed from GBGB1511017.4A external-priority patent/GB201511017D0/en
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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to certain benzylideneaminoguanidines for the treatment of fibrosis.
  • Tissue consists of cells and the extracellular space in between them. This space is primarily composed of a meshwork of proteins, e.g. collagen fibrils and proteoglycans such as decorin, versican and biglycan. Together these constitute the extracellular matrix (ECM). Sustaining tissue homeostasis is critical for maintaining the biochemical and structural support of cells provided by the ECM. Under normal conditions, wound healing or tissue repair is a tightly regulated process. Damaged connective tissue is replaced through synthesis of extracellular matrix (ECM) proteins produced by e.g. activated fibroblasts or myofibroblasts [1 , 2]. In fibrotic diseases, the regulatory mechanism is disrupted leading to excessive ECM synthesis and tissue fibrosis.
  • ECM extracellular matrix
  • Fibrotic disease of the lung such as idiopathic pulmonary fibrosis (IPF)
  • IPF idiopathic pulmonary fibrosis
  • the aetiology of fibrotic diseases is still unknown. However, some factors are associated with the development of fibrosis such as an ongoing autoimmune disease, exposure to radiation, chemotherapy and inhalation of asbestos.
  • TGF- ⁇ pro- fibrotic transforming growth factor beta-1
  • a-SMA alpha-smooth muscle actin
  • SLRPs small leucine-rich proteins
  • decorin in comparison to biglycan, showed a separate effect on cytoskeletal rearrangements with significantly increased expression of a-SMA, possibly connecting decorin to lung fibroblast activation.
  • the myofibroblast is abundant in so- called fibroblastic foci and it is recognized as a hallmark in certain types of pulmonary fibrotic diseases such as idiopathic pulmonary fibrosis [9].
  • serotonin (5- hydroxytryptamine (5-HT)
  • periphery where it is involved in e.g. regulation of vascular tone, platelet aggregation, immune response and bowel peristalsis [10, 1 1].
  • Peripheral 5-HT is mainly produced by the enterochromaffin cells of the gut and it is derived form tryptophan in a reaction catalysed by tryptophan hydroxylase-1 (Tph-1 ). Under physiological conditions, the level of free plasma 5-HT is low and strictly regulated by specific 5-HT transporters present on the surface of e.g. platelets.
  • Extracellular 5-HT is effectively transported into platelets where it is either degraded by 5-HT degrading enzymes or stored in dense granules [12].
  • 5-HT degrading enzymes or stored in dense granules [12].
  • platelets encounter, e.g. endothelial damage they become activated and aggregate, and release 5-HT resulting in an increase in local concentration [13].
  • the 5-HT 2 receptor family consists of 3 subtypes: 5-HT 2 A, 5-HT 2 B and 5- HT 2 c which have repeatedly been implicated in detrimental progressions of several diseases such as cardiovascular diseases.
  • the 5-HT 2B receptor has been linked to pulmonary artery hypertension (PAH) and the phenotype of the 5-HT 2B receptor knockout mice shows its importance for heart development [15, 16].
  • PAH pulmonary artery hypertension
  • the 5-HT 2 receptors have also been shown to be involved in e.g. fibrosis, inflammation and pain [17-25].
  • platelet-derived 5-HT is critical for normal wound healing where it stimulates both vasoconstriction and vasodilation, influences inflammatory responses and promotes formation of a temporary scar.
  • 5-HT 2 receptors have an important role in fibrotic disease by regulating production of pro- fibrotic mediators and modifying cell differentiation and activation [19, 23, 26].
  • 5-HT has been proposed to induce the expression of TGF- ⁇ [19, 27].
  • Dermal fibroblasts from patients diagnosed with systemic sclerosis have a dose-dependent increase of TGF- ⁇ mRNA in response to 5-HT as well as an increased expression of 5- HTR2B [19].
  • benzylideneaminoguanidines are capable of inhibiting myofibroblast differentiation and/or proteoglycan production and are therefore of use in the treatment of fibrosis. These benzylideneaminoguanidines are capable of interacting with one or more of the three serotonergic receptors 5HT 2A , 5HT 2B and 5HT 2C .
  • the invention provides a compound of general Formula I:
  • R1 , R2, R3, R4 and R5 is -S-R, wherein R is selected from alkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, and aryl having 6 to 10 carbon atoms, and wherein the other R1 , R2, R3, R4 and R5 groups are the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, hydroxy, cyano, nitro, trifluoroalkyl, amide, alkylamino having 2 to 6 carbon atoms, benzoyloxy, nitroxy, phenyl and sulpho; or a pharmacologically-acceptable salt thereof, for the treatment of fibrosis.
  • R1 , R2, R3, R4 and R5 is -S-R, wherein R is selected from alkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 6 carbon
  • R1 -R5 is -S-R.
  • R1 or R2 is -S-R. More preferably, only R1 or only R2 is -S-R.
  • R is selected from alkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, and aryl having 6 to 10 carbon atoms.
  • alkyl includes straight- and branched-chain hydrocarbon groups.
  • the "alkyl having 1 to 5 carbon atoms" is a lower alkyl such as methyl, ethyl, propyl or iso-propyl. Most preferably, alkyl is methyl.
  • alkoxy includes straight- and branched-chain alkoxy groups.
  • the "alkoxy having 1 to 5 carbon atoms" is a lower alkoxy such as methoxy, ethoxy, propoxy or iso-propoxy, most preferably methoxy.
  • At least one of R1 -R5 is halogen.
  • R1 -R5 is halogen.
  • the term halogen includes fluoro, chloro, bromo and iodo.
  • the halogen is fluoro or chloro.
  • R1 or R2 is halogen.
  • R1 is -S-R and R2 is halogen; or (ii) R1 is halogen and R2 is -S-R.
  • R3 is alkoxy, preferably methoxy.
  • R4 and R5 are both H. In some embodiments, R3, R4 and R5 are all H.
  • the trifluoroalkyi is trifluoromethyl, trifluoroethyl, trifluoropropyl or trifluoroiso- propyl.
  • alkylamino refers preferably to groups having 2-6 carbon atoms, particularly dialkylamino groups, and most preferably dimethylamino or diethylamino.
  • n is 0, 1 , 2 or 3, preferably 0 or 1 .
  • This linking group when present, may be saturated or unsaturated.
  • the following are preferred compounds of the invention:
  • N-(2-Chloro-3,4-dimethylthiophenylpropylideneamino)guanidine or a pharmacologically-acceptable salt thereof.
  • the following compounds are particularly preferred:
  • N-(2-chloro-4-methoxy-3-methylthiobenzylideneamino)guanidine referred to herein as COMP1
  • COMP1 N-(2-chloro-4-methoxy-3-methylthiobenzylideneamino)guanidine
  • the compounds of Formula (I) have basic properties and, consequently, they may be converted, if desired, to their therapeutically-active pharmaceutically-acceptable acid addition salts by treatment with appropriate acids, e.g. inorganic acids such as
  • hydrochloric hydrobromic, hydroiodic, sulphuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, succinic, fumaric, tartaric, citric, palmoic or para-toluene-sulphonic acid.
  • salt form may be converted into the free base form by treatment with alkali.
  • the invention also provides a pharmaceutical composition comprising:
  • the invention also provides for the use of a compound as defined herein in the manufacture of a medicament for the treatment of fibrosis.
  • the invention also provides a method of treating fibrosis comprising administering an effective amount of a compound as defined herein to a patient in need thereof.
  • Fibrosis is characterised by excessive connective tissue deposition.
  • fibrosis include pulmonary fibrosis (Interstitial Lung Disease, Idiopathic pulmonary fibrosis, Chronic Obstructive Pulmonary Fibrosis, etc.), liver fibrosis, heart fibrosis, kidney fibrosis, skin fibrosis and scleroderma.
  • the fibrosis is lung fibrosis or liver fibrosis, e.g. fibrotic disease of the lung or the liver.
  • Suitable forms of pharmaceutical preparation for administration include for example tablets, capsules, solutions, syrups, and emulsions.
  • the content of the pharmaceutically effective compound(s) in each case should desirably be in the range from 0.1 to 5 wt.%, of the total composition.
  • the preparations maybe administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension. It is preferable if the compounds of Formula (I) are administered orally.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known carriers, diluents or excipients, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets may also comprise several layers.
  • Coated tablets may suitably be prepared by coating cores produced similarly to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium
  • carboxymethyl cellulose carboxymethyl cellulose
  • wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • Excipients which may be used include, for example, water, pharmaceutically-acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g.
  • groundnut or sesame oil mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors,
  • mono- or polyfunctional alcohols e.g. ethanol or glycerol
  • carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors,
  • composition is preferably administered orally or by inhalation.
  • the tablets may contain, in addition to the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
  • the active substances may be combined with various flavour-enhancers or colourings in addition to the excipients mentioned above.
  • Figure 1 The in vitro experiment set-up.
  • FIG. 1 HFL-1 cells immunostained for the 5-HT 2 B receptor.
  • HFL-1 cells (A) untreated (x20 magnification), (B) treated 24h with TGF- ⁇ 10ng/ml + 5-HT 1 ⁇ (x10
  • Figure 3 Production of a-SMA in HFL-1 cells treated with fibrotic stimuli and 5-HT 2 B receptor antagonists.
  • (B) The relative quantity of intracellular a-SMA in HFL-1 cells was evaluated after treatment with 5-HT 2B receptor antagonists, COMP1 (10 ⁇ ) and COMP2 (10 ⁇ ). The antagonists were added either 1 h prior to (1 h pretreatment) or simultaneous with (no pretreatment) addition of fibrotic stimuli (TGF- ⁇ 10ng/ml + 5-HT 1 ⁇ ) (B). All samples were normalized to control; cells cultured in medium without added stimuli (A) or cells cultured in 10ng/ml TGF- ⁇ + ⁇ ⁇ 5-HT (B), n 4-5.
  • the protein was detected in stress fibres after 24h treatment with TGF- ⁇ 10ng/ml + 5-HT 1 ⁇ (green: anti-a-SMA antibody, blue: DAPI).
  • FIG. 4 Proteoglycan production in fibrotic stimulated HFL-1 cells treated with COMP1 and COMP2.
  • Cell culture medium from HFL-1 cells cultured in the presence of medium (control), TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇ (A) or co-cultured with TGF- ⁇ 10ng/ml + 5-HT 1 ⁇ and COMP1 or COMP2 were quantified for total amount proteoglycans (B) or total amount decorin (C).
  • FIG. 5 Lung tissue remodeling after p.o. treatment with 5-HT 2 B receptor antagonists in BLM-treated mice. Lung segments from bleomycin-treated mice were analyzed for lung tissue density after p.o. treatment with 5-HT 2 B receptor antagonists using
  • Tissue density was shown as positive stained tissue area vs total area (mm 2 ), % + SD.
  • HFL-1 Human foetal lung fibroblasts
  • ATCC Manassas, VA, U.S., cat.no. CCL-153
  • HFL-1 cells were cultured in Minimal Essential Medium (MEM), supplemented with 10U Penicillin, 0.1 mg/ml
  • the cell culture medium also contained 10% foetal clone III serum (FCIII) (Thermo Scientific, Waltham, MA, USA, cat. no. SH30109.03 ).
  • FCIII foetal clone III serum
  • the K, and IC 50 of the compounds were examined in Chinese hamster ovary (CHO) cells transfected with human recombinant 5-HT 2 receptors.
  • IC50 half maximal inhibitory concentration
  • Ki inhibition constant
  • 5-HT serotonin.
  • HFL-1 cells cultured 24h with or without fibrotic stimuli TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇ , 10 ⁇
  • TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇ , 10 ⁇ fibrotic stimuli
  • RNA amount and purity was measured with a
  • Hs00168362_m1 HTR2C (Hs00968671_m1 ) and GAPDH (Hs02758991_g1 ) from Applied Biosystems.
  • Gene expression levels were analysed by comparative Ct (cycle threshold) method, and related to endogenous control and total amount RNA. To identify cross contamination and genomic DNA, controls with RNA samples lacking reverse transcriptase and cDNA samples lacking DNA template were used. An initial analysis of four housekeeping genes was made to determine a stable endogenous control. Housekeeping genes GAPDH and 18S presented results indicative of stable gene expression and sufficient PCR efficiency, respectively (data not shown).
  • Immunocvtochemistry (ICC) Immunocvtochemistry
  • HFL-1 cells plated on glass chamber slides (Thermo Scientific) and cultured for 24h with or without fibrotic stimuli (TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇ ), were fixated in 4% buffered formaldehyde solution for 15 min in room temperature (RT).
  • fibrotic stimuli TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇
  • HFL-1 cells were labelled with anti-5HT 2 A receptor antibody ( ⁇ g/ml) (sc-166775, Santa Cruz, Dallas, TX, U.S.), anti-5-HT 2B receptor antibody (2.5Mg/ml) (AP01 188PU-N, Acris Antibodies GmbH, Herford, Germany) and anti-5-HT 2 c receptor antibody (PA5-27164, Thermo Scientific) for 90 min at RT, followed by washing in Tris-buffered saline (TBS). Cells were incubated with fluorescent-conjugated secondary antibodies (A-21428, A-21235; diluted 1/200; Life Technologies, Carlsbad, CA, USA) in combination with DAPI, for 45 min at RT. For localization of antibody labelled receptors, comparable studies were made with intact and permeabilized cells (conditioned 5min with 0.2% Triton-X100). Negative controls were composed of isotype matched antibodies (X0903, X0931 ;
  • Imaging processing was performed with imaging systems: Nikon Eclipse 80i, Nikon DSQiMC (Tokyo, Japan) and Olympus DP80 (Olympus, Center Valley, P.A., U.S.), with imaging software: NIS-Elements BR 3.2 Ink, cellSens Dimension (Olympus, Center Valley, P.A., U.S.) and ImageJ 1 .45s (Wayne Rasband, NIH, Bethesda, MD, U.S.). The expression of intracellular a-SMA was examined in equal manner in antibody labelled
  • HFL-1 cells seeded in 6-well cell culture plate, were pretreated (1 h) with COMP1 or COMP2 (10 ⁇ ) before addition of fibrotic stimuli (TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇ or 10 ⁇ ) or simultaneously treated with fibrotic stimuli and receptor antagonists. 24h post- treatment, cell lysate was collected with supplemented 1 % NP-40 (Sigma-Aldrich).
  • EXAMPLE 2 Lung fibroblasts expression of 5-HT 2 receptors
  • fibroblasts Lung fibroblasts (HFL-1 ) were shown to express the 5-HT 2 B receptor at both mRNA levels (data not shown) and protein levels (Fig. 2A). The mRNA level of 5-HTR2B was studied at 6, 24 and 48 h post-treatment of fibrotic stimuli, which displayed equivalent expression patterns.
  • the protein expression was sustained in TGF- ⁇ + 5-HT treated fibroblasts which also displayed a distinct cellular phenotype with protruding cellular outgrowths and an overall larger cellular size in comparison to untreated HFL-1 cells (Fig. 2B).
  • cells were permeabilized with Triton-X100 which revealed a distinct expression pattern separated from the pattern seen from intact cells (Fig. 2C).
  • HFL-1 cells were cultured to confluence in a 6-well cell culture plate following three stepwise culture treatments: Step 1 ) 2h culture in supplemented DMEM (1 % Amfotericin + 0.5% Gentamicin + 1 % Glutamine) with 1 % FCIII. Step 2) 2h culture in with TGF- ⁇ 10ng/ml ⁇ 5-HT 1 ⁇ and receptor antagonists in supplemented sulphate-poor medium (074-91083P, Invitrogen) containing 0.4% FCIII. Step 3) 22h culturing in 50 Ci/ml 35 S, following cell lysate and cell medium collection. Proteoglycans were extracted by column-based separation and size separated with gel electrophoresis according to previously described methodology [29].
  • mice Male, 12.5 weeks old were divided into seven mice per treatment group. Mice were s.c. injected three times a week with bleomycin (BLM, 50IE/animal) or saline solution for two weeks according to previous described methodology and housing conditions [30].
  • Compound-treated mice received daily p.o. administration of COMP1 or COMP2 solved in water-based Tween80 (Sigma Aldrich) solution (2.5(w/v) %) or 20% Solutol HS 15 (Sigma), in doses of 10mg/kg or 30mg/kg. All p.o. administrations were executed by the use of a 20 gauge silicone tipped feeding needle. Control animals received BLM or saline injections with p.o.
  • IHC IHC.
  • De-paraffin ized and re-hydrated lung segments (4 ⁇ ) were stained with hematoxylin/eosin according to standard protocol. Tissue density was analysed with ImageJ in randomly taken microscopic images of the lung parenchyma and assessed as total amount positive stained tissue area per total area (%). 7-10 randomly taken images per lung segment were processed as previously described in ICC methodology. All microscopic examinations were performed under sample coded conditions until finalization of analysis.
  • Monassier L Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts. Circulation 2004, 1 10(8):969- 974.

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Abstract

La présente invention concerne certaines benzylidène-aminoguanidines dans le traitement de la fibrose. Dans certains modes de réalisation préférés, la fibrose est la fibrose pulmonaire.
PCT/EP2015/069603 2014-08-29 2015-08-27 Aminoguanidines de formule (i) à utiliser dans le traitement de la fibrose Ceased WO2016030445A1 (fr)

Applications Claiming Priority (4)

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GB201415331A GB201415331D0 (en) 2014-08-29 2014-08-29 Method of treatment
GB1415331.6 2014-08-29
GBGB1511017.4A GB201511017D0 (en) 2015-06-23 2015-06-23 Method of treatment
GB1511017.4 2015-06-23

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008071980A1 (fr) * 2006-12-14 2008-06-19 Acure Pharma Ab Utilisation de nouvelles aminoguanidines comme ligands des récepteurs de la mélanocortine
WO2009080675A1 (fr) * 2007-12-20 2009-07-02 Glaxo Group Limited Dérivés de quinoline ayant une affinité pour le récepteur 5-ht2b

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008071980A1 (fr) * 2006-12-14 2008-06-19 Acure Pharma Ab Utilisation de nouvelles aminoguanidines comme ligands des récepteurs de la mélanocortine
WO2009080675A1 (fr) * 2007-12-20 2009-07-02 Glaxo Group Limited Dérivés de quinoline ayant une affinité pour le récepteur 5-ht2b

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
CERVANTES-DURAN C; PINEDA-FARIAS JB; BRAVO-HERNANDEZ M; QUINONEZ-BASTIDAS GN; VIDAL-CANTU GC; BARRAGAN-IGLESIAS P; GRANADOS-SOTO V: "Evidence for the participation of peripheral 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors in formalin-induced secondary mechanical allodynia and hyperalgesia", NEUROSCIENCE, 2012
CERVANTES-DURAN C; VIDAL-CANTU GC; BARRAGAN-IGLESIAS P; PINEDA-FARIAS JB; BRAVO-HERNANDEZ M; MURBARTIAN J; GRANADOS-SOTO V: "Role of peripheral and spinal 5-HT2B receptors in formalin-induced nociception", PHARMACOL BIOCHEM BEHAV, vol. 102, no. 1, 2012, pages 30 - 35
DEES C; AKHMETSHINA A; ZERR P; REICH N; PALUMBO K; HORN A; JUNGEL A; BEYER C; KRONKE G; ZWERINA J ET AL.: "Platelet-derived serotonin links vascular disease and tissue fibrosis", J EXP MED, vol. 208, no. 5, 2011, pages 961 - 972
DURK T; PANTHER E; MULLER T; SORICHTER S; FERRARI D; PIZZIRANI C; DI VIRGILIO F; MYRTEK D; NORGAUER J; IDZKO M: "5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes", INT IMMUNOL, vol. 17, no. 5, 2005, pages 599 - 606
FABRE A; MARCHAL-SOMME J; MARCHAND-ADAM S; QUESNEL C; BORIE R; DEHOUX M; RUFFIE C; CALLEBERT J; LAUNAY JM; HENIN D ET AL.: "Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice", EUR RESPIR J, vol. 32, no. 2, 2008, pages 426 - 436, XP009111740, DOI: doi:10.1183/09031936.00126907
GREWAL JS; MUKHIN YV; GARNOVSKAYA MN; RAYMOND JR; GREENE EL: "Serotonin 5-HT2A receptor induces TGF-beta1 expression in mesangial cells via ERK: proliferative and fibrotic signals", AM J PHYSIOL, vol. 276, no. 6, 1999, pages F922 - 930
HANAK V; RYU JH; DE CARVALHO E; LIMPER AH; HARTMAN TE; DECKER PA; MYERS JL: "Profusion of fibroblast foci in patients with idiopathic pulmonary fibrosis does not predict outcome", RESPIR MED, vol. 102, no. 6, 2008, pages 852 - 856, XP022631856, DOI: doi:10.1016/j.rmed.2008.01.012
HANNON JADH: "Serotonin receptors and systems: endless diversity?", ACTA BIOLOGICA SZEGEDIENSIS, vol. 46, no. 1-2, 2002, pages 1 - 12
HINZ B: "Formation and function of the myofibroblast during tissue repair", J INVEST DERMAFO/, vol. 127, no. 3, 2007, pages 526 - 537, XP055168201, DOI: doi:10.1038/sj.jid.5700613
HINZ B; PHAN SH; THANNICKAL VJ; GALLI A; BOCHATON-PIALLAT ML; GABBIANI G: "The myofibroblast: one function, multiple origins", AM J PATHOL, vol. 170, no. 6, 2007, pages 1807 - 1816
HUANG J; FAN Y; JIA Y; HONG Y: "Antagonism of 5-HT(2A) receptors inhibits the expression of pronociceptive mediator and enhances endogenous opioid mechanism in carrageenan-induced inflammation in rats", EUR J PHARMACOL, vol. 654, no. 1, 2011, pages 33 - 41
JAFFRE F; CALLEBERT J; SARRE A; ETIENNE N; NEBIGIL CG; LAUNAY JM; MAROTEAUX L; MONASSIER L: "Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts", CIRCULATION, vol. 110, no. 8, 2004, pages 969 - 974, XP009041442, DOI: doi:10.1161/01.CIR.0000139856.20505.57
KOENIGSHOFF MELANIE ET AL: "Increased expression of 5-hydroxytryptamine(2A/B) receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention", THORAX, vol. 65, no. 11, November 2010 (2010-11-01), pages 949 - 955, XP002745238, ISSN: 0040-6376 *
KONIGSHOFF M; DUMITRASCU R; UDALOV S; AMARIE OV; REITER R; GRIMMINGER F; SEEGER W; SCHERMULY RT; EICKELBERG O: "Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention", THORAX, vol. 65, no. 11, 2010, pages 949 - 955, XP002745238, DOI: doi:10.1136/thx.2009.134353
LIJNEN P; PETROV V: "Transforming growth factor-beta 1-induced collagen production in cultures of cardiac fibroblasts is the result of the appearance of myofibroblasts", METHODS FIND EXP CLIN PHARMACOL, vol. 24, no. 6, 2002, pages 333 - 344
LIN SY; CHANG WJ; LIN CS; HUANG CY; WANG HF; SUN WH: "Serotonin receptor 5-HT2B mediates serotonin-induced mechanical hyperalgesia", J NEUROSCI, vol. 31, no. 4, 2011, pages 141 0 - 1418
MANN DA; OAKLEY F: "Serotonin paracrine signaling in tissue fibrosis", BIOCHIM BIOPHYS ACTA, vol. 1832, no. 7, 2013, pages 905 - 910, XP028589906, DOI: doi:10.1016/j.bbadis.2012.09.009
MAULER M; BODE C; DUERSCHMIED D: "Platelet serotonin modulates immune functions", HAMOSTASEOLOGIE, vol. 35, no. 2, 2015
MERCADO CP; KILIC F: "Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels", MOL INTERV, vol. 10, no. 4, 2010, pages 231 - 241
NEBIGIL CG; CHOI DS; DIERICH A; HICKEL P; LE MEUR M; MESSADDEQ N; LAUNAY JM; MAROTEAUX L: "Serotonin 2B receptor is required for heart development", PROC NATL ACAD SCI U S A, vol. 97, no. 17, 2000, pages 9508 - 9513
NIHLBERG K; ANDERSSON-SJOLAND A; TUFVESSON E; ERJEFALT JS; BJERMER L; WESTERGREN-THORSSON G: "Altered matrix production in the distal airways of individuals with asthma", THORAX, vol. 65, no. 8, 2010, pages 670 - 676
RAGHU G: "Idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence-based in 2011", EUR RESPIR J, vol. 37, no. 4, 2011, pages 743 - 746
RAPPORT MM; GREEN AA; PAGE IH: "Serum vasoconstrictor, serotonin; isolation and characterization", J BIOL CHEM, vol. 176, no. 3, 1948, pages 1243 - 1251
ROY SG; NOZAKI Y; PHAN SH: "Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts", INT J BIOCHEM CELL BIOL, vol. 33, no. 7, 2001, pages 723 - 734
RYDELL-TORMANEN K; ANDREASSON K; HESSELSTRAND R; RISTELI J; HEINEGARD D; SAXNE T; WESTERGREN-THORSSON G: "Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis", LAB INVEST, vol. 92, no. 6, 2012, pages 917 - 925
SCHATTNER M: "Platelets and galectins", ANN TRANSL MED, vol. 2, no. 9, 2014, pages 85
SEIDEL MF; FIEBICH BL; ULRICH-MERZENICH G; CANDELARIO-JALIL E; KOCH FW; VETTER H: "Serotonin mediates PGE(2) overexpression through 5-HT(2A) and 5-HT (3) receptor subtypes in serum-free tissue culture of macrophage-like synovial cells", RHEUMATOL INT, 2008
THOMAS M; CIUCLAN L; HUSSEY MJ; PRESS NJ: "Targeting the serotonin pathway for the treatment of pulmonary arterial hypertension", PHARMACOL THER, vol. 138, no. 3, 2013, pages 409 - 417, XP028583601, DOI: doi:10.1016/j.pharmthera.2013.02.002
TUFVESSON E; WESTERGREN-THORSSON G: "Biglycan and decorin induce morphological and cytoskeletal changes involving signalling by the small GTPases RhoA and Rac1 resulting in lung fibroblast migration", J CELL SCI, vol. 116, 2003, pages 4857 - 4864
VENKATESAN N; ROUGHLEY PJ; LUDWIG MS: "Proteoglycan expression in bleomycin lung fibroblasts: role of transforming growth factor-beta(1 ) and interferon-gamma", AM J PHYSIOL LUNG CELL MOL PHYSIOL, vol. 283, no. 4, 2002, pages L806 - 814
VERRECCHIA F; MAUVIEL A: "Transforming growth factor-beta and fibrosis", WORLD J GASTROENTEROL, vol. 13, no. 22, 2007, pages 3056 - 3062, XP009137681

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