ITMI20130646A1 - CHINAZOLINDIONIC COMPOUNDS WITH INHABITING ACTIVITIES ON SIRTUINES - Google Patents
CHINAZOLINDIONIC COMPOUNDS WITH INHABITING ACTIVITIES ON SIRTUINES Download PDFInfo
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- ITMI20130646A1 ITMI20130646A1 IT000646A ITMI20130646A ITMI20130646A1 IT MI20130646 A1 ITMI20130646 A1 IT MI20130646A1 IT 000646 A IT000646 A IT 000646A IT MI20130646 A ITMI20130646 A IT MI20130646A IT MI20130646 A1 ITMI20130646 A1 IT MI20130646A1
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- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 description 1
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- FRUULBTYAKFASS-UHFFFAOYSA-N n-(2-benzylphenyl)-2,4-dioxo-1h-quinazoline-6-sulfonamide Chemical compound C1=C2C(=O)NC(=O)NC2=CC=C1S(=O)(=O)NC1=CC=CC=C1CC1=CC=CC=C1 FRUULBTYAKFASS-UHFFFAOYSA-N 0.000 description 1
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- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
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- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
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- OEAALAYSCPVHJC-UHFFFAOYSA-N quinazoline-2-sulfonyl chloride Chemical compound N1=C(N=CC2=CC=CC=C12)S(=O)(=O)Cl OEAALAYSCPVHJC-UHFFFAOYSA-N 0.000 description 1
- AHJBHKTZBNAQDR-UHFFFAOYSA-N quinazoline-6-sulfonamide Chemical compound N1=CN=CC2=CC(S(=O)(=O)N)=CC=C21 AHJBHKTZBNAQDR-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
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- 230000003938 response to stress Effects 0.000 description 1
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- ISFPDBUKMJDAJH-UHFFFAOYSA-N splitomicin Chemical compound C1=CC2=CC=CC=C2C2=C1OC(=O)CC2 ISFPDBUKMJDAJH-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
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- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
DESCRIZIONE DESCRIPTION
Il lavoro che ha condotto a questa invenzione ha ricevuto finanziamenti dal Settimo Programma Quadro dell’Unione Europea (FP7 2007-2013) sotto il grant agreement N° 256986. The work that led to this invention received funding from the Seventh Framework Program of the European Union (FP7 2007-2013) under the grant agreement No. 256986.
Campo di applicazione Field of application
La presente invenzione si riferisce al settore tecnico dell'industria farmaceutica e riguarda in particolare composti chinazolindionici con attività inibente sulle sirtuine, utili nel trattamento di diverse patologie, quali ad esempio patologie metaboliche, infiammatorie e tumorali. The present invention relates to the technical sector of the pharmaceutical industry and in particular relates to quinazolindionic compounds with inhibitory activity on sirtuins, useful in the treatment of various pathologies, such as for example metabolic, inflammatory and tumor pathologies.
Arte nota Known art
Le sirtuine sono enzimi NAD<+>-dipendenti, che svolgono un ruolo nell' invecchiamento, nel metabolismo, nel comportamento nutrizionale, nel cancro e nell'infiammazione<1>. A causa della loro ampia implicazione nella fisiopatologia di malattie altamente prevalenti, le sirtuine rappresentano un interessante target terapeutico<2>. Sirtuins are NAD <+> - dependent enzymes that play a role in aging, metabolism, nutritional behavior, cancer and inflammation <1>. Due to their wide implication in the pathophysiology of highly prevalent diseases, sirtuins represent an interesting therapeutic target <2>.
Sono note sette sirtuine (SIRT1-7) e sono stati descritti attivatori di SIRT1 con un ruolo potenzialmente positivo nella regolazione del metabolismo e nell'allungamento della durata di vita in salute ("healthspan"), sebbene la loro modalità d’azione sia ancora dibattuta<2>. Sono stati riportati anche inibitori di SIRT1, SIRT2 e SIRT5<3>. Seven sirtuins (SIRT1-7) are known, and activators of SIRT1 have been described with a potentially positive role in regulating metabolism and prolonging the life span in health ("healthspan"), although their mode of action is still debated <2>. Inhibitors of SIRT1, SIRT2 and SIRT5 <3> have also been reported.
SIRT6 è implicata nella stabilità genomica e la sua carenza è stata associata allo sviluppo di una sindrome progeroide nel topo<4>. SIRT6 promuove la riparazione del DNA mediante diversi meccanismi che comprendono la deacetilazione dell’istone H3 lisina 9 (H3K9) nella cromatina telomerica con conseguente associazione di WRN e mantenimento telomerico<5>, la stabilizzazione della proteinchinasi DNA-dipendente (DNA-PK) sulla cromatina<6>nonché la mono-ADP-ribosilazione della poli(ADP-ribosio)polimerasi 1 (PARP1) e la conseguente promozione della sua attività<7>. SIRT6 is implicated in genomic stability and its deficiency has been associated with the development of a progeroid syndrome in the <4> mouse. SIRT6 promotes DNA repair by several mechanisms including deacetylation of histone H3 lysine 9 (H3K9) in telomeric chromatin resulting in association of WRN and telomeric maintenance <5>, stabilization of DNA-dependent protein kinase (DNA-PK) on chromatin <6> as well as the mono-ADP-ribosylation of poly (ADP-ribose) polymerase 1 (PARP1) and the consequent promotion of its activity <7>.
Oltre a questo ruolo nella riparazione del DNA, SIRT6 regola la captazione del glucosio in virtù della sua capacità di co-reprimere il fattore di trascrizione Hifla, un regolatore critico delle risposte allo stress<8>. Le cellule con carenza di SIRT6 presentano un'attività Hifla incrementata, un aumento della captazione di glucosio e della glicolisi e una riduzione della respirazione mitocondriale. In addition to this role in DNA repair, SIRT6 regulates glucose uptake by virtue of its ability to co-repress the transcription factor Hifla, a critical regulator of stress responses <8>. SIRT6-deficient cells exhibit increased Hifla activity, increased glucose uptake and glycolysis, and decreased mitochondrial respiration.
In linea con questi riscontri, topi con carenza di SIRT6 sviluppano ipoglicemia e presentano un marcato incremento della captazione di glucosio nel tessuto muscolare e nel tessuto adiposo bruno<4>·<8>. Consistent with these findings, SIRT6-deficient mice develop hypoglycemia and have markedly increased glucose uptake in muscle tissue and brown adipose tissue <4> · <8>.
Infine, SIRT6 svolge un ruolo nell' infiammazione, come dimostrato dai difetti immunologie! di topi SIRT6-deficienti<4>e dalla capacità di promuovere l'espressione di TNFa, IFN-γ<10>e IL8<11>in risposta a stimoli attivatori. L'attività immunogenica di SIRT6 riflette, almeno in parte, la sua propensione ad aumentare i livelli di ADP-ribosio intracellulare in virtù della sua attività enzimatica<12>. A sua volta, l'ADP-ribosio derivato dalla SIRT6 sembra promuovere le risposte al Ca<2+>, la trascrizione dei geni delle citochine (attraverso il fattore di trascrizione NFAT) e la motilità cellulare. Finally, SIRT6 plays a role in inflammation, as demonstrated by immunological defects! of SIRT6-deficient mice <4> and the ability to promote the expression of TNFα, IFN-γ <10> and IL8 <11> in response to activating stimuli. The immunogenic activity of SIRT6 reflects, at least in part, its propensity to increase intracellular ADP-ribose levels by virtue of its <12> enzymatic activity. In turn, SIRT6-derived ADP-ribose appears to promote Ca <2+> responses, transcription of cytokine genes (via the transcription factor NFAT) and cell motility.
L'inibizione di SIRT6 appare dunque costituire una strategia percorribile per il trattamento del cancro (quale mezzo per sensibilizzare le cellule cancerose agli agenti antitumorali e alla radioterapia e per ridurre infiammazione associata al cancro)<4>·<6>·<12>, di disturbi metabolici (in virtù della sua capacità di aumentare la captazione tissutale di glucosio) e dell'infiammazione. Tuttavia finora non sono stati descritti inibitori specifici di SIRT6 laddove la disponibilità di inibitori di SIRT6 selettivi potrebbe portare all’ ottenimento di agenti terapeutici con ampia possibilità di applicazione The inhibition of SIRT6 therefore appears to constitute a viable strategy for the treatment of cancer (as a means of sensitizing cancer cells to anticancer agents and radiotherapy and to reduce inflammation associated with cancer) <4> · <6> · <12>, metabolic disorders (by virtue of its ability to increase tissue glucose uptake) and inflammation. However, so far no specific inhibitors of SIRT6 have been described where the availability of selective SIRT6 inhibitors could lead to the obtainment of therapeutic agents with a wide range of application
La domanda di brevetto WO 2008/138943 si riferisce ad un inibitore di sirtuine diverso dalla suramina per l'utilizzo nella riduzione di TNF-alfa e/o nella riduzione infiammazione locale o sistemica in un soggetto e/o nel trattamento di patologie mediate da TNF-alfa. L'inibitore in questione è scelto tra sfilinolo, m-sirtinolo, p-sirtinolo, splitomicina, deidrosplitomicina, cambinolo e diidrocumarina. Patent application WO 2008/138943 refers to a sirtuins inhibitor other than suramine for use in the reduction of TNF-alpha and / or in the reduction of local or systemic inflammation in a subject and / or in the treatment of pathologies mediated by TNF -alpha. The inhibitor in question is selected from strinol, m-sirtinol, p-sirtinol, splitomycin, dehydrosplitomycin, cambinol and dihydrocumarin.
La domanda di brevetto WO 2011/038110 riguarda l’uso di un inibitore di SIRT6 per ridurre o inibire l’iperglicemia o l'obesità in un soggetto. Tra gli inibitori di SIRT6 si citano anticorpi anti-SIRT6, molecole di RNA interferenti e acidi nucleici anti-senso. Patent application WO 2011/038110 relates to the use of a SIRT6 inhibitor to reduce or inhibit hyperglycemia or obesity in a subject. SIRT6 inhibitors include anti-SIRT6 antibodies, interfering RNA molecules and anti-sense nucleic acids.
Sommario dell' invenzione Summary of the invention
II problema alla base della presente invenzione è stato quello di mettere a disposizione composti provvisti di attività inibente nei confronti delle sirtuine, in particolare, anche se non esclusivamente, di SIRT6, per l'utilizzo nell’induzione della captazione tissutale del glucosio (e quindi per ottenere una riduzione dei livelli di glicemia) e/o nella riduzione della produzione di TNF-alfa e di altre citochine proinfiammatorie, chemiotattiche, o pro-angiogeniche (come IFN-γ e IL8) e/o nell’interferire con la riparazione del DNA in cellule tumorali, così da poter essere utilizzati come agenti terapeutici nel trattamento di patologie legate al diabete di tipo I o II e/o di patologie infiammatorie e/o di patologie neoplastiche. The problem underlying the present invention was that of providing compounds with inhibitory activity towards sirtuins, in particular, although not exclusively, SIRT6, for use in the induction of tissue glucose uptake (and therefore to obtain a reduction in blood glucose levels) and / or in the reduction of the production of TNF-alpha and other proinflammatory, chemotactic, or pro-angiogenic cytokines (such as IFN-γ and IL8) and / or in interfering with the repair of the DNA in tumor cells, so that they can be used as therapeutic agents in the treatment of pathologies related to type I or II diabetes and / or inflammatory pathologies and / or neoplastic pathologies.
Un tale problema è stato risolto secondo l'invenzione dalla messa a disposizione dei composti di formula (I) Such a problem has been solved according to the invention by making available the compounds of formula (I)
in cui: in which:
R<1>= H, C1-C3alchile; R <1> = H, C1-C3alkyl;
R<2>= H, C1-C3alchile; R <2> = H, C1-C3alkyl;
R<3>, R<4>, R<5>, R<6>sono scelti indipendentemente tra H, Ci-ealchile, C3-6cicloalchile, alogeno, NO2, CN, OH, SH, CF3,CCI3, COOH, COOCi-s alchile, SO2OC1 5alchile, OC1-5alchile, fenile eventualmente sostituito, fenossile eventualmente sostituito, Ci-salchilfenile eventualmente sostituito sull’anello benzenico, un anello eterociclico saturo o aromatico a 5 o 6 membri contenente uno o più eteroatomi scelti tra N, S e O, NR<7>R<8>o un gruppo G-R<10>, dove R <3>, R <4>, R <5>, R <6> are independently chosen from H, C1-alkyl, C3-6cycloalkyl, halogen, NO2, CN, OH, SH, CF3, CCI3, COOH, COOCi -s alkyl, SO2OC1 5alkyl, OC1-5alkyl, phenyl optionally substituted, phenoxy optionally substituted, Cis-salkylphenyl optionally substituted on the benzene ring, a saturated or aromatic heterocyclic ring with 5 or 6 members containing one or more heteroatoms selected from N, S and O, NR <7> R <8> or a group G-R <10>, where
R<7>e R<8>sono indipendentemente H o Ci-s alchile, R <7> and R <8> are independently H or Ci-s alkyl,
G = SOaNR<9>, CONR<9>, NR<9>S02, NR<9>CO, 0, (CH2)n, NH, CO, S, O-(CH2)m, S-(CH2)m, (CH2)m-0, (CH2)m-S, -NH-C=NH, -C0-CH2-0, CO-NH-{CH2)n, dove n = l-3 e m = l o 2 G = SOaNR <9>, CONR <9>, NR <9> S02, NR <9> CO, 0, (CH2) n, NH, CO, S, O- (CH2) m, S- (CH2) m , (CH2) m-0, (CH2) m-S, -NH-C = NH, -C0-CH2-0, CO-NH- {CH2) n, where n = l-3 and m = l or 2
R<9>= H, Ci-salchile, R <9> = H, Ci-salchyl,
in cui R<11>= Ci-6alchile, C3-6cicloalchile, alogeno, N02, CN, OH, SH, CF3,CC13, COOH, COOC1-5alchile, S02OCi-5alchile, OCi-5alchile, fenile eventualmente sostituito, fenossile eventualmente sostituito, Ci- wherein R <11> = C1-6alkyl, C3-6cycloalkyl, halogen, N02, CN, OH, SH, CF3, CC13, COOH, COOC1-5alkyl, SO2OCi-5alkyl, OCi-5alkyl, possibly substituted phenyl, possibly substituted phenoxy , There-
3alchilfenile eventualmente sostituito sull’anello benzenico, oppure Y- 3alkylphenyl possibly substituted on the benzene ring, or Y-
R12, R12,
in cui Y = un legame semplice, -O-, -CH2-, e where Y = a simple bond, -O-, -CH2-, e
R<12>= un anello eterociclico saturo o aromatico a 5 o 6 membri contenente uno o più eteroatomi scelti tra N, S e O, eventualmente sostituito da un Ci-Csalchile, R <12> = a 5- or 6-membered saturated or aromatic heterocyclic ring containing one or more heteroatoms selected from N, S and O, possibly replaced by a C-Csalkyl,
a condizione che uno dei sostituenti R<3>, R<4>, R<5>, R<6>sia un gruppo G-R<10>come definito sopra, provided that one of the substituents R <3>, R <4>, R <5>, R <6> is a group G-R <10> as defined above,
o suoi enantiomeri, diastereoisomeri e sali farmaceuticamente accettabili, per l'uso come medicamento. or its enantiomers, diastereomers and pharmaceutically acceptable salts, for use as a medicament.
Per "alchile” si intendono sia gli alchili a catena lineare sia quelli a catena ramificata. By "alkyl" is meant both straight-chain and branched-chain alkyls.
Preferibilmente nei composti di formula (I) i sostituenti hanno i seguenti significati: Preferably in the compounds of formula (I) the substituents have the following meanings:
R<1>= H, CH3R <1> = H, CH3
R2 = H, CH3R2 = H, CH3
in cui R<11>= fenile, fenossile, benzile oppure Y-R<12>, wherein R <11> = phenyl, phenoxy, benzyl or Y-R <12>,
in cui Y = un legame semplice, -O-, -CH2-, e where Y = a simple bond, -O-, -CH2-, e
R12 = piridinile o imidazolile. R12 = pyridinyl or imidazolyl.
Secondo una forma di realizzazione preferita, i composti della presente invenzione presentano la seguente formula (II) According to a preferred embodiment, the compounds of the present invention have the following formula (II)
(Π) (Π)
in cui in which
R<1>= H, C1-C3 alchile; R <1> = H, C1-C3 alkyl;
R<2>= H, C1-C3 alchile; R <2> = H, C1-C3 alkyl;
RIO = RIO =
in cui R<1 1>= Ci-6alchile, C 3 -eciclo alchile, alogeno, NO2, CN, OH, SH, CF3,CCI3, COOH, COOCi-5alchile, S020C1.5alchile, OC 1-5 alchile, fenile eventualmente sostituito, fenossile eventualmente sostituito, Ci-3alchilfenile eventualmente sostituito sull'anello benzenico, oppure Y-R^2, wherein R <1 1> = Ci-6alkyl, C 3 -ecyclo alkyl, halogen, NO2, CN, OH, SH, CF3, CCI3, COOH, COOCi-5alkyl, S020C1.5alkyl, OC 1-5 alkyl, phenyl optionally substituted, optionally substituted phenoxy, C-3alkylphenyl optionally substituted on the benzene ring, or Y-R ^ 2,
in cui Y = un legame semplice, -O-, -CH2-, e where Y = a simple bond, -O-, -CH2-, e
RÌ2 =unanello eterociclico saturo o aromatico a 5 o 6 membri contenente uno o più eteroatomi scelti tra N, S e O, eventualmente sostituito da un CnCsalchile, RÌ2 = a saturated or aromatic heterocyclic ring with 5 or 6 members containing one or more heteroatoms selected from N, S and O, optionally substituted by a CnCsalkyl,
In maniera ulteriormente preferita, i composti di formula (I) comprendono i seguenti composti: Further preferably, the compounds of formula (I) comprise the following compounds:
(1) 2,4-diosso-N-[4-(piridin~3-ilossi)fenil]-l,2,3,4~ tetraidrochinazolina-6-soIfonammide; (1) 2,4-dioxo-N- [4- (pyridine ~ 3-yloxy) phenyl] -1, 2,3,4 ~ tetrahydroquinazoline-6-soIphonamide;
(2) N-[4-( lH-imidazol- l-ilmetil)fenil]~2,4-diosso- 1, 2,3,4-tetraidrochinazolina~6- solfo nammide ; (2) N- [4- (1H-imidazol- 1-ylmethyl) phenyl] ~ 2,4-dioxo- 1, 2,3,4-tetrahydroquinazoline ~ 6-sulphonamide;
(3) 2,4-dìosso-N-{3-[2-(piridin-4-il)etil]fenil}-l,2,3,4-tetraidrochinazolina-6- solfonammide ; (3) 2,4-dioxo-N- {3- [2- (pyridine-4-yl) ethyl] phenyl} -1, 2,3,4-tetrahydroquinazoline-6-sulfonamide;
(4) N-(2-benzilfenil)-2,4-diosso- 1,2,3, 4-tetraidrochinazolina-6- solfonammide; (4) N- (2-benzylphenyl) -2,4-dioxo- 1,2,3,4-tetrahydroquinazoline-6-sulfonamide;
(5) 2,4-diosso-N-(2-fenilfenil)-l,2,3,4-tetraidrochinazolina-6-solfonammide; (5) 2,4-dioxo-N- (2-phenylphenyl) -1, 2,3,4-tetrahydroquinazoline-6-sulfonamide;
(6) 1 ,3-dimetil-2,4-diosso-N-[4-(piridin-4-ilmetil)fenil)-1.2.3.4-tetraidrochinazolina-6-solfonammide; o (6) 1,3-dimethyl-2,4-dioxo-N- [4- (pyridine-4-ylmethyl) phenyl) -1.2.3.4-tetrahydroquinazoline-6-sulfonamide; or
(7) N-(2H-l,3-benzodioxol-5-yl)-l,3-dimethyl~2,4-dioxo-1.2.3 .4- tetrahy dro quinazoline- 6- sulfonamide . (7) N- (2H-1,3-benzodioxol-5-yl) -1, 3-dimethyl ~ 2,4-dioxo-1.2.3 .4- tetrahy dro quinazoline- 6- sulfonamide.
I composti di formula (I) sopra menzionati possono essere utilizzati come inibitori di una o più sirtuine, e in particolare di SIRT6, per aumentare la captazione tessutale del glucosio in un soggetto. The compounds of formula (I) mentioned above can be used as inhibitors of one or more sirtuins, and in particular of SIRT6, to increase the tissue uptake of glucose in a subject.
Secondo un aspetto della presente invenzione, tali composti possono essere utilizzati nel trattamento di: According to an aspect of the present invention, such compounds can be used in the treatment of:
diabete mellito di tipo I e di tipo II e delle relative complicanze, quali coma chetoacidosico, stato iperglicemico iperosmolare, aterosclerosi, malattia cardiaca ischemica (angina e infarto miocardico), ictus, vasculopatia periferica, retinopatia diabetica, nefropatia diabetica, neuropatia diabetica e piede diabetico. type I and type II diabetes mellitus and related complications, such as ketoacidosic coma, hyperosmolar hyperglycemic state, atherosclerosis, ischemic heart disease (angina and myocardial infarction), stroke, peripheral vasculopathy, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic foot .
Secondo un altro aspetto della presente invenzione, i composti di formula (I) possono essere utilizzati come inibitori di una o più sirtuine, e in particolare di SIRT6, per ridurre la produzione di TNF-alfa e di altre citochine pro-infiammatorie, chemio tattiche, o proangiogeniche (come IFN-γ e IL8) in un soggetto e/o ridurre infiammazione locale o sistemica in un soggetto e/o trattare una patologia mediata da TNF-alfa o da altre citochine pro-infiammatorie, chemio tattiche, o pro-angiogeniche (come IFN-γ e IL8) in un soggetto che presenti una produzione di citochine locale o sistemica eccessiva o deregolata. According to another aspect of the present invention, the compounds of formula (I) can be used as inhibitors of one or more sirtuins, and in particular of SIRT6, to reduce the production of TNF-alpha and other pro-inflammatory cytokines, chemo tactics , or proangiogenic (such as IFN-γ and IL8) in a subject and / or reduce local or systemic inflammation in a subject and / or treat a pathology mediated by TNF-alpha or other pro-inflammatory cytokines, chemo tactics, or pro angiogenics (such as IFN-γ and IL8) in a subject with excessive or deregulated local or systemic cytokine production.
Di conseguenza tali composti trovano applicazione nel trattamento di malattie infiammatorie comprendenti artrite reumatoide, sclerosi multipla, malattia infiammatoria intestinale, lupus eritematosus sistemico, vasculite, sindrome di Goodpasture, scleroderma, aterosclerosi, malattia del trapianto verso l'ospite (GVHD), rigetto di trapianto d'organo, infarto del miocardio, ictus, danno da riperfusione dopo rivascolarizzazione nel cuore e in altri organi. Consequently, these compounds find application in the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, Goodpasture's syndrome, scleroderma, atherosclerosis, graft versus host disease (GVHD), transplant rejection. organ, myocardial infarction, stroke, reperfusion injury after revascularization in the heart and other organs.
Secondo un ulteriore aspetto della presente invenzione, i composti di formula (I) sono utilizzati come inibitori di una o più sirtuine, e in particolare di SIRT6, per interferire con la riparazione del DNA in cellule tumorali e quindi esercitare un effetto antitumorale e sensibilizzare dette cellule ad agenti antineoplastici e alla radioterapia. Di conseguenza tali composti trovano applicazione nel trattamento di malattie neoplastiche comprendenti cancro pancreatico, cancro mammario, cancro colorettale, cancro prò statico, cancro ovarico, melanoma, cancro polmonare, cancro esofageo, epatocarcinoma, linfomi, leucemie, mieloma, sarcomi, cachessia neoplastica. According to a further aspect of the present invention, the compounds of formula (I) are used as inhibitors of one or more sirtuins, and in particular of SIRT6, to interfere with DNA repair in tumor cells and therefore exert an antitumor effect and sensitize said cells to antineoplastic agents and radiotherapy. Consequently, these compounds find application in the treatment of neoplastic diseases including pancreatic cancer, breast cancer, colorectal cancer, prostatic cancer, ovarian cancer, melanoma, lung cancer, esophageal cancer, hepatocarcinoma, lymphomas, leukemias, myeloma, sarcomas, neoplastic cachexia.
In un ulteriore aspetto, la presente invenzione riguarda una composizione farmaceutica contenente una quantità terapeuticamente efficace di almeno un composto di formula (I) o di un suo enantiomero, diastereoisomero o sale farmaceuticamente accettabile, come sopra definito e un veicolo farmaceuticamente accettabile. In a further aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula (I) or its pharmaceutically acceptable enantiomer, diastereomer or salt, as defined above, and a pharmaceutically acceptable vehicle.
Esempi di sali farmaceuticamente accettabili sono quelli formati con acidi organici quali ossalico, tartarico, maleico, succinico e citrico e con acidi inorganici quali nitrico, cloridrico, solforico e fosforico. Examples of pharmaceutically acceptable salts are those formed with organic acids such as oxalic, tartaric, maleic, succinic and citric and with inorganic acids such as nitric, hydrochloric, sulfuric and phosphoric.
I composti secondo l’invenzione che hanno uno o più atomi di carbonio asimmetrici possono esistere come enantiomeri puri, come diastereoisomeri puri, come miscele racemiche di enantiomeri, racemati e miscele di racemati. The compounds according to the invention that have one or more asymmetric carbon atoms can exist as pure enantiomers, as pure diastereomers, as racemic mixtures of enantiomers, racemates and mixtures of racemates.
I composti e le composizioni secondo l’invenzione possono essere somministrati con qualunque sistema di rilascio disponibile ed efficace, comprese, in maniera non limitativa, le vie orale, buccale, parenterale, inalatoria, l’applicazione topica, per iniezione, per via transdermica o rettale (ad es. mediante suppositori) in formulazioni di unità di dosaggio contenenti convenzionali supporti farmaceuticamente accettabili e non tossici, adiuvanti e veicolanti. La somministrazione per via parenterale comprende iniezione sottocutanea, endovenosa, intramuscolare, intrasternale o tecniche di infusione. The compounds and compositions according to the invention can be administered with any available and effective delivery system, including, but not limited to, oral, buccal, parenteral, inhalation, topical, injection, transdermal or rectal (e.g. by suppositories) in dosage unit formulations containing conventional pharmaceutically acceptable and non-toxic carriers, adjuvants and carriers. Parenteral administration includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques.
Le forme di dosaggio solide per la somministrazione per via orale comprendono ad esempio capsule, compresse, polveri, granuli e gel. In tali forme di dosaggio solide il composto attivo può essere miscelato con almeno un diluente inerte come ad esempio saccarosio, lattosio o amido. Normalmente queste forme di dosaggio comprendono anche sostanze addizionali diverse dai diluenti inerti, come ad esempio agenti lubrificanti tipo il magnesio stearato. Solid dosage forms for oral administration include, for example, capsules, tablets, powders, granules and gels. In such solid dosage forms the active compound can be mixed with at least one inert diluent such as for example sucrose, lactose or starch. Normally these dosage forms also include additional substances other than inert diluents, such as lubricating agents such as magnesium stearate.
Le preparazioni iniettabili, ad esempio soluzioni o sospensioni acquose o oleose, sterili iniettabili possono essere formulate secondo la tecnica nota e utilizzando eventualmente appropriati agenti disperdenti, bagnanti e/o sospendenti. The injectable preparations, for example aqueous or oily solutions or suspensions, sterile injectable can be formulated according to the known art and possibly using appropriate dispersing, wetting and / or suspending agents.
Le preparazioni farmaceutiche secondo la presente invenzione possono essere prodotte mediante l’utilizzo delle tecniche farmaceutiche convenzionali, come descritte nelle varie farmacopee o in manuali del settore come ad esempio “Remington’s Pharmaceutical Sciences Handbook”, Mack Publishing, New York, 18th Ed., 1990. The pharmaceutical preparations according to the present invention can be produced by using conventional pharmaceutical techniques, as described in the various pharmacopoeias or in manuals of the sector such as "Remington's Pharmaceutical Sciences Handbook", Mack Publishing, New York, 18th Ed., 1990 .
II dosaggio medio giornaliero dei composti secondo la presente invenzione dipende da molti fattori, quali ad esempio la gravità della malattia e le condizioni del paziente (età, peso, sesso): La dose può variare generalmente da 1 mg a 1500 mg di composto secondo l’invenzione al giorno, eventualmente suddivisi in più somministrazioni. The average daily dosage of the compounds according to the present invention depends on many factors, such as for example the severity of the disease and the condition of the patient (age, weight, sex): The dose can generally vary from 1 mg to 1500 mg of compound according to the invention per day, possibly divided into several administrations.
Infine, in un ulteriore aspetto, la presente invenzione riguarda un metodo per ridurre la produzione di TNF-alfa e di altre citochine proinfiammatorie, chemio tattiche, o pro-angiogeniche in cellule in vitro, comprendente la fase di esporre le cellule a un composto come sopra definito, un metodo per aumentare la captazione di glucosio in cellule in vitro, comprendente la fase di esporre le cellule a un suddetto composto, così come un metodo per aumentare effetto antiproliferativo e citotossico di farmaci antineoplastici e di radiazioni ionizzanti in vitro, comprendente la fase di esporre le cellule tumorali a un suddetto composto. Finally, in a further aspect, the present invention relates to a method for reducing the production of TNF-alpha and other proinflammatory, chemo tactical, or pro-angiogenic cytokines in cells in vitro, comprising the step of exposing the cells to a compound such as defined above, a method for increasing glucose uptake in cells in vitro, comprising the step of exposing cells to a said compound, as well as a method for increasing antiproliferative and cytotoxic effect of antineoplastic drugs and ionizing radiation in vitro, comprising the step of exposing the cancer cells to such a compound.
Con i composti secondo la presente invenzione possono essere preparate formulazioni farmaceutiche per il trattamento di diverse condizioni patologiche mediate da sirtuine e in particolare da SIRT6. Alcune di queste malattie, come il diabete mellito di tipo II, le malattie neoplastiche e quelle infiammatorie hanno un fortissimo impatto epidemiologico e pertanto le formulazioni farmaceutiche contenenti i composti secondo la presente invenzione sono suscettibili di vasto impiego in diversi settori della terapia medica, con i vantaggi tecnici, economici e produttivi legati al fatto di essere basate su molecole organiche a basso peso molecolare e stabili. Pharmaceutical formulations for the treatment of various pathological conditions mediated by sirtuins and in particular by SIRT6 can be prepared with the compounds according to the present invention. Some of these diseases, such as type II diabetes mellitus, neoplastic and inflammatory diseases have a very strong epidemiological impact and therefore the pharmaceutical formulations containing the compounds according to the present invention are amenable to wide use in various sectors of medical therapy, with technical, economic and production advantages linked to the fact that they are based on stable, low molecular weight organic molecules.
Le formulazioni possono inoltre comprendere anche altri principi attivi o possono essere utilizzate in combinazione con altre formulazioni contenenti altri principi attivi, quali ad esempio antiinfiammatori, ipoglicemizzanti, chemioterapici, oppure la radioterapia. The formulations can also comprise other active ingredients or can be used in combination with other formulations containing other active ingredients, such as for example anti-inflammatory, hypoglycemic, chemotherapy, or radiotherapy.
Descrizione dettagliata Detailed description
I composti di formula (II) sopra descritti possono essere preparati a partire da corrispondenti 6~clorosolfonil-chinazolin~2,4-dioni di formula The compounds of formula (II) described above can be prepared starting from corresponding 6 ~ chlorosulfonyl-quinazolin ~ 2,4-diones of formula
per reazione con R<10>-NH2, by reaction with R <10> -NH2,
in cui R<1>, R<2>e R<10>sono come definiti in relazione ai composti di formula (II). wherein R <1>, R <2> and R <10> are as defined in relation to the compounds of formula (II).
La reazione viene condotta nelle condizioni descritte in Kuryazov R. Sh. et al, Chemistry of Heterocyclic Compounds, Voi. 44, No. The reaction is carried out under the conditions described in Kuryazov R. Sh. et al, Chemistry of Heterocyclic Compounds, Vol. 44, No.
3, 2008 "Quinazolines 1. Synthesis and Chemical reactions of 6-chlorosulfonyi-quinazoline-2 ,4-diones" . 3, 2008 "Quinazolines 1. Synthesis and Chemical reactions of 6-chlorosulfonyi-quinazoline-2, 4-diones".
I composti preferiti più sopra menzionati sono disponibili in commercio dalle seguenti fonti: The preferred compounds mentioned above are commercially available from the following sources:
(1): dalla ditta Asinex, identificativo del prodotto: (1): from the company Asinex, product identifier:
SYN17739303; SYN17739303;
(2): dalla ditta Asinex, identificativo del prodotto: SYN 17738896; (2): from the company Asinex, product identifier: SYN 17738896;
(3): dalla ditta Asinex, identificativo del prodotto: SYN 17742030; (3): from the company Asinex, product identification: SYN 17742030;
(4): dalla ditta Asinex, identificativo del prodotto: SYN 17736818; (4): from the company Asinex, product identifier: SYN 17736818;
(5): dalla ditta Asinex, identificativo del prodotto: SYN 17735999; (5): from the company Asinex, product identification: SYN 17735999;
(6): dalla ditta Princeton BioMolecular Research, Ine, identificativo del prodotto: OSSL_304544; (6): from Princeton BioMolecular Research, Ine, product identifier: OSSL_304544;
(7): dalla ditta Princeton BioMolecular Research, Ine, identificativo del prodotto: OSSL_299760. (7): from Princeton BioMolecular Research, Ine, product identifier: OSSL_299760.
Con il termine "soggetto” ci si riferisce, nella presente domanda, ad animali, preferibilmente mammiferi e in maniera particolarmente preferita a individui umani. The term "subject" refers, in the present application, to animals, preferably mammals and particularly preferably to human individuals.
Con il termine "trattare" o "trattamento" si intende sia un trattamento terapeutico sia un trattamento preventivo, profilattico, così come ad un trattamento che consegue un prolungamento della sopravvivenza rispetto a quello atteso in assenza di trattamento. The term "treat" or "treatment" means both a therapeutic treatment and a preventive, prophylactic treatment, as well as a treatment that results in a prolongation of survival compared to that expected in the absence of treatment.
L'espressione "quantità terapeuticamente efficace" si riferisce ad una quantità in grado di determinare una risposta biologica o terapeutica in un tessuto o sistema animale o umano ricercata da un ricercatore, medico o veterinario e che, in particolare, possa prevenire o alleviare almeno un sintomo locale o sistemico della malattia trattata. The expression "therapeutically effective amount" refers to an amount capable of causing a biological or therapeutic response in an animal or human tissue or system sought by a researcher, doctor or veterinarian and which, in particular, can prevent or alleviate at least one local or systemic symptom of the disease being treated.
L'attività dei composti secondo la presente invenzione è stata valutata mediante una serie di test biologici e in particolare quelli riassunti qui di seguito. The activity of the compounds according to the present invention was evaluated by means of a series of biological tests and in particular those summarized below.
Test di inibizione delle sirtuine Sirtuins inhibition test
L'attività in vitro dei composti secondo la presente invenzione in termini di inibizione delle sirtuine è stata determinata utilizzando kit commerciali per SIRT6, SIRT1 e SIRT2 disponibili dalla ditta Cayman, Ann Arbor, USA, seguendo le istruzioni del produttore. The in vitro activity of the compounds according to the present invention in terms of inhibition of sirtuins was determined using commercial kits for SIRT6, SIRT1 and SIRT2 available from the company Cayman, Ann Arbor, USA, following the manufacturer's instructions.
Sono stati determinati i valori di IC50 utilizzando i saggi in kit commerciali. Tutti i composti sono stati soìubilizzati a concentrazione 50 mM in DMSO. Le concentrazioni dei composti nelle misurazioni per la determinazione della IC50 erano nell’intervallo da 8 μΜ a 5 mM. I valori di IC50 sono stati determinati dalle curve di regressione non lineari logaritmiche mediante GraphPad Prism (GraphPad Software, La Jolla, CA - USA). Sono state eseguite tre misurazioni indipendenti di IC50 per ciascun composto. IC50 values were determined using commercial kit assays. All the compounds were soubilized at a concentration of 50 mM in DMSO. The concentrations of the compounds in the measurements for the determination of the IC50 were in the range from 8 μΜ to 5 mM. IC50 values were determined from logarithmic nonlinear regression curves using GraphPad Prism (GraphPad Software, La Jolla, CA - USA). Three independent measurements of IC50 were performed for each compound.
Analisi Western Blot. Western Blot Analysis.
Cellule di adenocarcinoma pancreatico BxPC3 sono state incubate per 18 ore con i vari composti (concentrazione finale 100 μΜ). Le cellule sono state lisate in tampone di lisi (Tris-HCL 50 mM, pH 7,5, NaCl 150 mM, NP40 1% e cocktail di inibitori di proteasi) e 30 pg di proteine sono state caricate su gel di poliacrilammide al 15% e separate mediante SDS-PAGE. Le proteine sono state trasferite su membrane di nitrocellulosa e incubate con l'anticorpo primario specifico contro la H3K9 acetilata (Sigma, Milano) e con l'anticorpo contro l'actina (Santa Cruz Biotechnology, Santa Cruz, USA). In seguito a incubazione con gli appropriati anticorpi secondari e alla rilevazione ECL (GE Healthcare, Milano), è stata misurata l'intensità della banda con il sistema di imaging ChemiDoc (BioRad) e il livello di acetilazione H3K9 è stato normalizzato all'actina. BxPC3 pancreatic adenocarcinoma cells were incubated for 18 hours with the various compounds (final concentration 100 μΜ). Cells were lysed in lysis buffer (50mM Tris-HCL, pH 7.5, 150mM NaCl, 1% NP40 and protease inhibitor cocktail) and 30µg of proteins loaded onto 15% polyacrylamide gel. and separated by SDS-PAGE. The proteins were transferred onto nitrocellulose membranes and incubated with the specific primary antibody against acetylated H3K9 (Sigma, Milan) and with the antibody against actin (Santa Cruz Biotechnology, Santa Cruz, USA). Following incubation with the appropriate secondary antibodies and ECL detection (GE Healthcare, Milan), the intensity of the band was measured with the ChemiDoc Imaging System (BioRad) and the H3K9 acetylation level was normalized to actin.
Effetti sul TNF-alfa Effects on TNF-alpha
Cellule BxPC-3 sovraesprimenti SIRT6 {Bauer I. et al., J. Biol. Chem. 2012 Oct 18) (3 x 10<s>cellule/pozzetto) sono state seminate in piastre a 6 pozzetti e lasciate aderire per 24 ore prima di essere incubate per 18 ore con i vari composti (concentrazione finale 100 μΜ). Successivamente, per indurre l'espressione di citochine, le cellule sono state stimolate per 48 ore con 25 ng/ml di forbolo miristilato acetato (PMA; Sigma Aldrich). Successivamente i surnatanti sono stati raccolti e saggiati per IL8 e TNF utilizzando kit ELISA disponibili in commercio DuoSet® (R&D Systems, Minneapolis, USA). La concentrazione nei surnatanti è stata normalizzata alla densità cellulare misurata con sulforodamina B. BxPC-3 cells overexpressing SIRT6 {Bauer I. et al., J. Biol. Chem. 2012 Oct 18) (3 x 10 <s> cells / well) were seeded in 6-well plates and allowed to adhere for 24 hours before being incubated for 18 hours with the various compounds (final concentration 100 μΜ). Subsequently, to induce cytokine expression, the cells were stimulated for 48 hours with 25 ng / ml phorbol myristylate acetate (PMA; Sigma Aldrich). The supernatants were then collected and tested for IL8 and TNF using commercially available DuoSet® ELISA kits (R&D Systems, Minneapolis, USA). Concentration in supernatants was normalized to cell density measured with sulforodamine B.
Esperimenti di captazione del glucosio Glucose uptake experiments
1 x IO<5>cellule BxPC-3 ingegnerizzate per esprimere il vettore pRETROSUPER (pRS) o un shRNA mirato a SIRT6 (sh2 SIRT6) (Bauer I, et al. J Biol Chem. 2012 Oct 18.) sono state piastrate in ogni pozzetto di una piastra a 12 pozzetti in 500 pL di mezzo di coltura standard. 72 ore dopo le cellule sono state incubate (o non incubate) in presenza dei composti ad una concentrazione di 200 μΜ per 18 h. Le cellule sono state poi lavate una volta con 1 mi di tampone PBS ed è stato misurato il trasporto di glucosio mediante aggiunta di D-glucosio/[<14>C]-2-deossi-D-glucosio 0.5 mM (0.2 pCi/pozzetto) in tampone KRH per 5 min a 37°C. La captazione (uptake) di glucosio è stata arrestata eliminando immediatamente la miscela di marcatura e lavando le cellule 3 volte con KRH ghiacciato. Le cellule sono state poi lisate con sodio dodecilsolfato (SDS) 0.1% e un'aliquota di ciascun lisato è stata utilizzata per il conteggio in scintillazione in un Beta-Counter LS 6500 (Beckman-Coulter,CA). La captazione aspecifica in presenza di citocalasina B 20 μΜ e floretina 200 μΜ è stata sottratta a ciascun valore sperimentale. 1 x IO <5> BxPC-3 cells engineered to express the pRETROSUPER vector (pRS) or a SIRT6 targeted shRNA (sh2 SIRT6) (Bauer I, et al. J Biol Chem. 2012 Oct 18.) were plated in each well of a 12-well plate in 500 µL of standard culture medium. 72 hours later the cells were incubated (or not incubated) in the presence of the compounds at a concentration of 200 μΜ for 18 h. The cells were then washed once with 1 ml of PBS buffer and glucose transport was measured by adding 0.5 mM D-glucose / [<14> C] -2-deoxy-D-glucose (0.2 pCi / well ) in KRH buffer for 5 min at 37 ° C. Glucose uptake was stopped by immediately removing the labeling mixture and washing the cells 3 times with ice-cold KRH. The cells were then lysed with 0.1% sodium dodecyl sulfate (SDS) and an aliquot of each lysate was used for scintillation counting in a Beta-Counter LS 6500 (Beckman-Coulter, CA). Nonspecific uptake in the presence of cytochalasin B 20 μΜ and phloretin 200 μΜ was subtracted from each experimental value.
Saggio di autoADP-ribosilazione di SIRT6 SIRT6 autoADP-ribosylation assay
Le reazioni sono state eseguite in un volume totale di 10 μΐ, contenenti 20 pg di SIRT6 ricombinante (prodotta seguendo protocolli pubblicati<13>) in 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 10 mM ditiotreitolo, e 0.4 pCi [<3>H]NAD (40 Ci mmol-1; Perkin Elmer, Boston, MA), in presenza o assenza dei diversi composti (200 μΜ, concentrazione finale) o di nicotinammide (100 mM, concentrazione finale) per 45 min a 22 °C. Alla fine dell’incubazione, i campioni sono stati filtrati su una membrana di nitrocellulosa (Bio-Rad), i filtri sono stati lavati due volte con 3 mi di tampone di lavaggio (50 mM Tris-HCl, pH 8.0, 150 mM NaCl) e poi asciugati e la radioattivita’ e’ stata misurata in 3.0 mi Ultima-Gold con un β-counter Packard. The reactions were performed in a total volume of 10 μΐ, containing 20 pg of recombinant SIRT6 (produced following published protocols <13>) in 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 10 mM dithiothreitol, and 0.4 pCi [ <3> H] NAD (40 Ci mmol-1; Perkin Elmer, Boston, MA), in the presence or absence of the different compounds (200 μΜ, final concentration) or nicotinamide (100 mM, final concentration) for 45 min at 22 ° C. At the end of the incubation, the samples were filtered on a nitrocellulose membrane (Bio-Rad), the filters were washed twice with 3 ml of wash buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl) and then dried and the radioactivity was measured in 3.0 ml Ultima-Gold with a Packard β-counter.
La seguente tabella riassume i dati sperimentali ottenuti sottoponendo alcuni composti secondo la presente invenzione ai test sopra illustrati. The following table summarizes the experimental data obtained by subjecting some compounds according to the present invention to the tests illustrated above.
* = percentuale di inibizione di SIRT6 ≥ 10% e < 30%; * = percentage of inhibition of SIRT6 ≥ 10% and <30%;
** = percentuale di inibizione di SIRT6 > 30% e < 70% ** = percentage of inhibition of SIRT6> 30% and <70%
*** = percentuale di inibizione di SIRT6 > 70%. *** = percentage of inhibition of SIRT6> 70%.
I dati sopra riportati dimostrano che i composti secondo la presente invenzione presentano attività inibitoria nei confronti delle sirtuine SIRT1, SIRT2 e SIRT6, con una buona selettività nei confronti di SIRT6, così come un'attività inibitoria nei confronti della produzione di TNF-alfa da parte di cellule BxPC3; una capacità di aumentare l’uptake di glucosio in cellule BxPC3; una (modesta) capacità di ridurre rautoADP-ribosilazione di SIRT6; e una capacità di ridurre la vitalità di cellule BxPC3 in presenza di una bassa concentrazione di gemcitabina (1 nM), che di per sé risulterebbe inattiva in assenza di inibitori di SIRT6 (% di inibizione della vitalità da parte di gemcitabina 1 nM da sola = 4%). The above data show that the compounds according to the present invention show inhibitory activity towards the sirtuins SIRT1, SIRT2 and SIRT6, with a good selectivity towards SIRT6, as well as an inhibitory activity towards the production of TNF-alpha by of BxPC3 cells; an ability to increase glucose uptake in BxPC3 cells; a (modest) ability to reduce the autoADP-ribosylation of SIRT6; and an ability to reduce viability of BxPC3 cells in the presence of a low concentration of gemcitabine (1 nM), which itself would be inactive in the absence of SIRT6 inhibitors (% inhibition of viability by gemcitabine 1 nM alone = 4%).
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| WO2002064572A1 (en) * | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Llc | Quinazolines as mmp-13 inhibitors |
| WO2008138943A2 (en) * | 2007-05-14 | 2008-11-20 | Universite Libre De Bruxelles | Prophylactic and therapeutic use of sirtuin inhibitors in tnf-alpha mediated pathologies |
| WO2011038110A2 (en) * | 2009-09-23 | 2011-03-31 | The General Hospital Corporation | Methods of treating metabolic disease |
| WO2011106114A1 (en) * | 2010-02-19 | 2011-09-01 | Senomyx, Inc. | Identification of human t2r receptors and the use thereof to identify inhibitors (blockers) of bitter taste |
| US20120115846A1 (en) * | 2009-04-09 | 2012-05-10 | Sanofi | Quinazolinedione derivatives, preparation thereof and various therapeutic uses thereof. |
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| WO2002064572A1 (en) * | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Llc | Quinazolines as mmp-13 inhibitors |
| WO2008138943A2 (en) * | 2007-05-14 | 2008-11-20 | Universite Libre De Bruxelles | Prophylactic and therapeutic use of sirtuin inhibitors in tnf-alpha mediated pathologies |
| US20120115846A1 (en) * | 2009-04-09 | 2012-05-10 | Sanofi | Quinazolinedione derivatives, preparation thereof and various therapeutic uses thereof. |
| WO2011038110A2 (en) * | 2009-09-23 | 2011-03-31 | The General Hospital Corporation | Methods of treating metabolic disease |
| WO2011106114A1 (en) * | 2010-02-19 | 2011-09-01 | Senomyx, Inc. | Identification of human t2r receptors and the use thereof to identify inhibitors (blockers) of bitter taste |
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| CURRENT OPINION IN INVESTIGATIONAL DRUGS (LONDON, ENGLAND : 2000) APR 2010, vol. 11, no. 4, April 2010 (2010-04-01), pages 447 - 454, ISSN: 2040-3429 * |
| DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; April 2010 (2010-04-01), DOTSON CEDRICK D ET AL: "T1R and T2R receptors: the modulation of incretin hormones and potential targets for the treatment of type 2 diabetes mellitus.", XP002718182, Database accession no. NLM20336593 * |
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