ITMI20111068A1 - Trimetilangelicina come correttore di cftr in cellule dell'epitelio bronchiale - Google Patents
Trimetilangelicina come correttore di cftr in cellule dell'epitelio bronchiale Download PDFInfo
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- ITMI20111068A1 ITMI20111068A1 IT001068A ITMI20111068A ITMI20111068A1 IT MI20111068 A1 ITMI20111068 A1 IT MI20111068A1 IT 001068 A IT001068 A IT 001068A IT MI20111068 A ITMI20111068 A IT MI20111068A IT MI20111068 A1 ITMI20111068 A1 IT MI20111068A1
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- cftr
- cystic fibrosis
- tma
- inflammatory
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Description
“TRIMETILANGELICINA COME CORRETTORE DI CFTR IN CELLULE DELL’EPITELIO BRONCHIALEâ€
DESCRIZIONE
La presente invenzione si riferisce all’impiego di uno psoralene angolare, la trimetilangelicina (4,6,4’-trimetilangelicina - TMA), quale molecola in grado di correggere la localizzazione intracellulare della forma mutata della proteina di membrana denominata CFTR (da Cystic Fibrosis Transmembrane conductance Regulator) alterata nei tessuti di pazienti affetti da fibrosi cistica; si propone tale molecola per la preparazione di un medicamento per il trattamento terapeutico della fibrosi cistica (CF).
Stato della tecnica
La fibrosi cistica à ̈ una malattia genetica autosomica recessiva causata da mutazioni del gene che codifica CFTR. L’incidenza della malattia nella popolazione caucasica à ̈ di 1/2000-3000 nuovi nati, mentre à ̈ molto inferiore nei nativi africani ed asiatici (1). Per queste ragioni, la scoperta di molecole in grado di correggere e/o potenziare il CFTR riveste una grande importanza nello sviluppo di terapie innovative per la fibrosi cistica.
D’altra parte l’impiego di molecole allo scopo di inibire il processo infiammatorio cronico nelle vie respiratorie di soggetti affetti da fibrosi cistica à ̈ effettuato da tempo. Nella maggior parte dei casi, tali molecole sono state applicate alla patologia infiammatoria cronica delle vie respiratorie nella fibrosi cistica dopo un uso consolidato in altre patologie infiammatorie croniche, sistemiche o locali, non necessariamente delle vie respiratorie. Le prime molecole utilizzate sono stati i farmaci anti-infiammatori corticosteroidei, quali il prednisolone per via sistemica (2) oppure il fluticasone propionato (3) ed il beclometasone (4) per via inalatoria.
Successivamente, molecole anti-infiammatorie quali ibuprofene sono state largamente applicate (5,6), come pure macrolidi quali azitromicina (7,8). Inoltre, allo scopo di ottenere un efficace effetto anti-infiammatorio, altre molecole sono state studiate a livello sperimentale, quali l’antiossidante N-acetilcisteina (9) e l’antagonista dei recettori dei leucotrieni montelukast (10), per citare i più noti. In sintesi, in diversi casi l’effetto anti-infiammatorio à ̈ stato correlato in studi clinici controllati con un significativo miglioramento oppure un rallentato decadimento della funzionalità respiratoria, mentre i principali limiti applicativi hanno riguardato l’insorgenza di effetti indesiderati sulla funzione corticosurrenale, oppure renale o gastrointestinale.
Rispetto al trattamento antiinfiammatorio, una terapia diretta a ridurre l’espressione di IL-8 nel trattamento di pazienti affetti da fibrosi cistica potrebbe pertanto ridurre gli effetti negativi indotti dal processo infiammatorio, anche se à ̈ necessario combinare tale attività con quella di altre molecole in grado di correggere gli effetti delle mutazioni che causano inattività della proteina CFTR. Questa necessità riguarda una coorte importante di pazienti, nei quali l’attività del CFTR à ̈ particolarmente disregolata.
Abbiamo precedentemente dimostrato che un analogo della angelicina, la trimetilangelicina, à ̈ un potente inibitore del processo infiammatorio indotto in cellule fibrocistiche da P. aeruginosa e un potente potenziatore di CFTR (11). Di interesse à ̈ l’osservazione che l’attività antiinfiammatoria à ̈ notevolmente superiore a quella di altri psoraleni correntemente utilizzati in terapia clinica di patologie infiammatorie croniche della cute, come ad esempio 5-metossipsoralene (5-MOP) ed 8-metossipsoralene (8-MOP)(11).
Descrizione dell’invenzione
Si à ̈ ora sorprendentemente scoperto che la trimetilangelicina (TMA) à ̈ un potente correttore di CFTR. Questo effetto à ̈ inatteso e non descritto precedentemente studiando psoraleni lineari ed angolari, oggetto di studio da decenni anche su cellule fibrocistiche. Pertanto, la stessa molecola (TMA) possiede tre attività , tutte di interesse per la terapia della fibrosi cistica: attività antiinfiammatoria, attività potenziatrice di CFTR e attività di correzione di CFTR.
La formula di struttura della TMA, paragonata all’angelicina e al composto 8-MOP e 5-MOP (scelti a titolo esemplificativo tra gli psoraleni lineari), à ̈ la seguente:
Trimetilangelicina (TMA)
Angelicina (2-oxo-(2H)-furo(2,3-H)-1-benzopirano)
8-metossipsoralene(8-MOP) 5-metossipsoralene (5-MOP) In particolare, i risultati pregressi ottenuti hanno dimostrato che TMA inibisce l’accumulo di mRNA per IL-8 in cellule epiteliali bronchiali IB3-1 in seguito ad infezione con P. aeruginosa (11). IB3-1 à ̈ una linea cellulare derivata dall’epitelio bronchiale, immortalizzata con adeno12/SV40 e derivata da un paziente CF con genotipo F508del/W1282X (12). Parallelamente TMA possiede un effetto potenziatore di CFTR.
L’ attività di correzione di CFTR, che sta alla base dell’invenzione, à ̈ inaspettata alla luce degli utilizzi terapeutici noti di analoghi strutturali di TMA (13-24).
La sintesi chimica di TMA e, più in generale degli psoraleni, à ̈ stata descritta da diversi gruppi di ricerca (si vedano ad esempio i riferimenti bibliografici n. 15-18).
Un primo oggetto della presente invenzione à ̈ pertanto trimetilangelicina per l’uso come correttore di CFTR in pazienti affetti da fibrosi cistica.
D’altra parte, un trattamento combinato con diversi modificatori del processo infiammatorio potrebbe permettere di incrementare la risposta biologica e clinica alla terapia.
Perciò, un secondo oggetto della presente invenzione à ̈ una combinazione di trimetilangelicina (TMA) con almeno un’ulteriore molecola ad azione anti-infiammatoria per l’uso nel trattamento della fibrosi cistica oppure con un altro correttore o potenziatore di CFTR, quale ad esempio il correttore VX809 e il potenziatore N-(2,4-di-ter-butyl-5-hydroxyphenyl)4-oxo-1,4-dihydroquinoline-3-carboxamide (VX770).
Esempi di modificatori del processo infiammatorio comprendono azitromicina e ibuprofene.
La TMA, da sola o associata a detti farmaci, potrà essere somministrata per via orale o aerosolica; esempi di formulazioni adatte alla somministrazione orale comprendono capsule, compresse, sciroppi, soluzioni o sospensioni bevibili e simili forme di dosaggio convenzionali. Per la somministrazione aerosol, forme di dosaggio adatte comprendono soluzioni, sospensioni o polveri da somministrare con l’ausilio di dispositivi convenzionali quali i cosiddetti MDI (metered dose inhalers), eventualmente utilizzando opportuni veicoli gassosi quali HFA.
I dosaggi di TMA saranno determinati dagli esperti del settore sulla base dei tests farmacodinamici e farmacocinetici, dipenderanno inoltre dal peso, dall’età e dalle condizioni del paziente e da altri parametri che saranno determinati dal medico curante. In linea di massima, le dosi efficaci potranno essere comprese nell'intervallo da circa 10 a circa 500 mg, preferibilmente da circa 10 a circa 250 mg di TMA al giorno, eventualmente suddivise in più somministrazioni, anche se non si possono escludere dosaggi inferiori o superiori.
La TMA potrà essere somministrata per mezzo di opportuni sistemi di delivery, allo scopo di facilitare l’effetto di correzione/potenziamento del CFTR rispetto all’effetto antiinfiammatorio, in relazione al genotipo/fenotipo del paziente.
L’attività di TMA come correttore di CFTR à ̈ stata dimostrata valutando l’efflusso di cloro, misurato mediante spettrofluorimetria. Inoltre l’uso di anticorpi monoclonali per CFTR ha permesso di mettere in evidenza la correzione della localizzazione intracellulare, portando la proteina CFTR mutata sulla membrana plasmatica.
L’invenzione à ̈ illustrata in maggior dettaglio negli esempi seguenti. ESEMPIO 1: Ripristino dell’efflusso di cloro CFTR-mediato in monolayers polarizzati di cellule CFBE41o- incubate per 24 ore con TMA 100 nM
L’efflusso di cloro à ̈ stato misurato mediante spettrofluorimetria dopo pre-incubazione dei monostrati di cellule bronchiolari FC omozigoti per la mutazione F508del CFTR con il fluoroforo MQAE (5mM), sensibile alla concentrazione intracellulare di cloro. I risultati sono riportati in Figura 1. Nell’istogramma à ̈ riportato la media dei valori di efflusso di cloro CFTR-mediato calcolato come la differenza tra efflusso di cloro indotto dall’attivazione della proteinchinasi-AMP ciclico dipendente (PKA) indotta da forskolin (FSK 10 µM) in assenza e presenza dell’inibitore specifico CFTRinh-172 (5 µM). L’efflusso di cloro CFTR-dipendente in cellule trattate per 24 ore con il TMA (100 nanomolare) à ̈ significativamente differente dalla media dei valori ottenuti in cellule bronchiolari FC di controllo o trattate con il solo solvente (3% DMSO/Metanolo).
ESEMPIO 2: cellule CFBE41o-, trattate o no con TMA 100 nM per 24 ore
Monostrati polarizzati di cellule bronchiolari FC non permeabilizzate erano marcate con l’anticorpo primario monoclonale CF3 che riconosce il primo loop extracellulare del CFTR. Come à ̈ evidente in figura 2, (riquadro a destra) solo i monostrati cellulari preincubati per 24 ore con TMA (100 nanomolare) mostrano una significativa marcatura della proteina mutata F508del CFTR in membrana.
Bibliografia
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Claims (4)
- RIVENDICAZIONI 1. Trimetilangelicina (TMA) per l’uso come correttore di CFTR in pazienti affetti da fibrosi cistica.
- 2. Formulazioni per il trattamento della fibrosi cistica che comprendono l’associazione di trimetilangelicina con almeno un altro modificatore del processo infiammatorio e/o con un altro correttore o potenziatore di CFTR.
- 3. Formulazioni secondo la rivendicazione 2 in cui l’altro modificatore del processo infiammatorio à ̈ ibuprofene oppure azitromicina.
- 4. Formulazioni secondo la rivendicazione 2 in cui il correttore di CFTR Ã ̈ VX809 e il potenziatore di CFTR Ã ̈ VX770.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT001068A ITMI20111068A1 (it) | 2011-06-14 | 2011-06-14 | Trimetilangelicina come correttore di cftr in cellule dell'epitelio bronchiale |
| CA2839134A CA2839134A1 (en) | 2011-06-14 | 2012-06-13 | Trimethylangelicin as cftr corrector in bronchial epithelial cells |
| PCT/EP2012/061193 WO2012171954A1 (en) | 2011-06-14 | 2012-06-13 | Trimethylangelicin as cftr corrector in bronchial epithelial cells |
| EP12734825.8A EP2720694A1 (en) | 2011-06-14 | 2012-06-13 | Trimethylangelicin as cftr corrector in bronchial epithelial cells |
| US14/125,109 US9283206B2 (en) | 2011-06-14 | 2012-06-13 | Trimethylangelicin as CFTR corrector in bronchial epithelial cells |
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| IT001068A ITMI20111068A1 (it) | 2011-06-14 | 2011-06-14 | Trimetilangelicina come correttore di cftr in cellule dell'epitelio bronchiale |
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| US (1) | US9283206B2 (it) |
| EP (1) | EP2720694A1 (it) |
| CA (1) | CA2839134A1 (it) |
| IT (1) | ITMI20111068A1 (it) |
| WO (1) | WO2012171954A1 (it) |
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| DK3219705T3 (da) | 2005-12-28 | 2020-04-14 | Vertex Pharma | Farmaceutiske sammensætninger af den amorfe form af n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamid |
| US9221840B2 (en) | 2011-05-17 | 2015-12-29 | Discoverybiomed Inc. | Treating protein folding disorders with small molecule CFTR correctors |
| MX355183B (es) | 2012-01-25 | 2018-04-09 | Vertex Pharma | Formulaciones de acido 3- (6- (1- (2.2- difluorobenzo [d] [1,3] dioxol-5-il) ciclopropancarboxamido) -3- metilpiridin-2-il) benzoico. |
| WO2014081820A1 (en) | 2012-11-20 | 2014-05-30 | Discoverybiomed, Inc. | Small molecule cftr correctors |
| EP2922853A4 (en) | 2012-11-20 | 2016-11-23 | Discoverybiomed Inc | SMALL MOLECULE BICYCLIC AND TRICYCLIC CFTR CORRECTING DEVICES |
| CA2903107C (en) | 2013-03-15 | 2021-11-02 | Discoverybiomed, Inc. | Coumarin derivatives and methods of use in treating hyperproliferative diseases |
| MX372775B (es) * | 2013-03-15 | 2020-06-29 | Discoverybiomed Inc | Derivados de cumarina y métodos de uso en el tratamiento de la fribosis quística, enfermedad pulmonar obstructiva crónica y trastornos de proteínas mal plegadas. |
| CN107250113B (zh) | 2014-10-07 | 2019-03-29 | 弗特克斯药品有限公司 | 囊性纤维化跨膜传导调节蛋白的调节剂的共晶 |
| EP3226861A2 (en) | 2014-12-05 | 2017-10-11 | Centre National de la Recherche Scientifique (CNRS) | Compounds for treating cystic fibrosis |
| US20170100374A1 (en) * | 2015-10-09 | 2017-04-13 | AbbVie S.à.r.l. | Potentiator-corrector combinations useful in the treatment of cystic fibrosis |
| AU2019334684B2 (en) | 2018-09-09 | 2025-03-06 | Qanatpharma Ag | Use of CFTR modulators for treating cerebrovascular conditions |
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-
2011
- 2011-06-14 IT IT001068A patent/ITMI20111068A1/it unknown
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2012
- 2012-06-13 CA CA2839134A patent/CA2839134A1/en not_active Abandoned
- 2012-06-13 US US14/125,109 patent/US9283206B2/en not_active Expired - Fee Related
- 2012-06-13 EP EP12734825.8A patent/EP2720694A1/en not_active Withdrawn
- 2012-06-13 WO PCT/EP2012/061193 patent/WO2012171954A1/en not_active Ceased
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Also Published As
| Publication number | Publication date |
|---|---|
| US20150290167A1 (en) | 2015-10-15 |
| US9283206B2 (en) | 2016-03-15 |
| EP2720694A1 (en) | 2014-04-23 |
| WO2012171954A1 (en) | 2012-12-20 |
| CA2839134A1 (en) | 2012-12-20 |
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