ITMI20100118A1 - USE OF RECEPTOR AGONISTS AND ANTAGONISTS FOR GROWTH HORMONE SECRETAGOGUES FOR THE PREVENTION AND TREATMENT OF CONVULSIONS AND EPILEPSY - Google Patents
USE OF RECEPTOR AGONISTS AND ANTAGONISTS FOR GROWTH HORMONE SECRETAGOGUES FOR THE PREVENTION AND TREATMENT OF CONVULSIONS AND EPILEPSY Download PDFInfo
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- ITMI20100118A1 ITMI20100118A1 IT000118A ITMI20100118A ITMI20100118A1 IT MI20100118 A1 ITMI20100118 A1 IT MI20100118A1 IT 000118 A IT000118 A IT 000118A IT MI20100118 A ITMI20100118 A IT MI20100118A IT MI20100118 A1 ITMI20100118 A1 IT MI20100118A1
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- lys
- convulsions
- epilepsy
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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Description
“USO DI AGONISTI E ANTAGONISTI DEI RECETTORI PER I GROWTH HORMONE SECRETAGOGUES PER LA PREVENZIONE E IL TRATTAMENTO DI CONVULSIONI ED EPILESSIA†⠀ œ USE OF AGONISTS AND RECEPTOR ANTAGONISTS FOR GROWTH HORMONE SECRETAGOGUES FOR THE PREVENTION AND TREATMENT OF CONVULSIONS AND EPILEPSYâ €
Campo tecnico dell’invenzione Technical field of invention
La presente invenzione riguarda l’utilizzo agonisti e antagonisti dei recettori per i growth hormone secretagogues (GHS), da soli o in associazione con altri composti anticonvulsivanti o antiepilettici, per la prevenzione e il trattamento di patologie convulsive e di stati epilettici. The present invention relates to the use of agonists and antagonists of receptors for growth hormone secretagogues (GHS), alone or in association with other anticonvulsant or antiepileptic compounds, for the prevention and treatment of convulsive diseases and epileptic states.
Stato della tecnica State of the art
Allo stato attuale l’approccio terapeutico alle convulsioni, causate da patologie epilettiche o da patologie di altra natura associate a manifestazioni convulsive, prevede l’impiego di farmaci che deprimono il sistema nervoso centrale e inducono sonnolenza e diminuzione dello stato di veglia. At present, the therapeutic approach to convulsions, caused by epileptic diseases or other pathologies associated with convulsive manifestations, involves the use of drugs that depress the central nervous system and induce drowsiness and decreased wakefulness.
In una percentuale rilevante di pazienti (fino al 30%) la patologia non risponde a tale terapia farmacologica. In a relevant percentage of patients (up to 30%) the disease does not respond to this drug therapy.
Con il termine “crisi convulsive†si intende comprendere una varietà di sintomi neurologici dovuti ad un’attività di scarica elettrica anomala, sincronizzata e prolungata, che coinvolge cellule nervose della corteccia o del tronco cerebrale e comporta disturbi delle funzioni motorie, sensoriali e/o intellettive. The term `` convulsive crisis '' means to understand a variety of neurological symptoms due to an abnormal, synchronized and prolonged electrical discharge activity, which involves nerve cells of the cortex or brain stem and involves disturbances of motor, sensory and / or intellectual.
Il 5% della popolazione sperimenta almeno una crisi convulsiva nell’arco della vita, pur non essendo necessariamente affetta da epilessia. 5% of the population experiences at least one seizure in their lifetime, even though they are not necessarily affected by epilepsy.
La diagnosi di epilessia implica il riscontro di crisi convulsive ripetute, le quali si osservano nello 0,5% della popolazione. The diagnosis of epilepsy implies the finding of repeated seizures, which are observed in 0.5% of the population.
In base alla sintomatologia clinica e al tracciato elettroencefalografico (EEG) delle crisi convulsive, si distinguono epilessie generalizzate (le scariche anomale iniziano contemporaneamente nei due emisferi cerebrali) ed epilessie parziali o focali (le scariche anomale iniziano in una determinata parte del cervello). Based on the clinical symptoms and the electroencephalographic (EEG) tracing of the seizures, we distinguish generalized epilepsies (abnormal discharges start simultaneously in the two cerebral hemispheres) and partial or focal epilepsies (abnormal discharges begin in a specific part of the brain).
Quando le scariche iniziano localmente per poi diffondersi a tutto il cervello si parla di epilessia secondaria generalizzata. When the discharges begin locally and then spread to the whole brain, it is called secondary generalized epilepsy.
Normalmente, le crisi convulsive si risolvono spontaneamente entro pochi minuti. Seizures usually resolve spontaneously within minutes.
Quando la crisi convulsiva perdura per un tempo prolungato o quando due o più crisi si presentano in modo ravvicinato senza che il soggetto riprenda conoscenza (cluster di convulsioni) si ha la condizione di stato di male epilettico che rappresenta (soprattutto quando le crisi sono di tipo convulsivo) un'emergenza medica che richiede una terapia immediata. When the seizure lasts for a prolonged time or when two or more seizures occur in close proximity without the subject regaining consciousness (cluster of convulsions) there is the condition of epileptic status that represents (especially when the seizures are of the type convulsive) a medical emergency that requires immediate therapy.
Stati epilettici protratti possono essere letali perché possono portare a grave insufficienza respiratoria. Prolonged epileptic states can be lethal because they can lead to severe respiratory failure.
Oltre ad essere suddivise secondo il tipo di crisi, le epilessie vengono classificate in sindromi epilettiche, che raggruppano determinati tipi di crisi con altri aspetti clinici caratteristici. In addition to being divided according to the type of seizure, epilepsies are classified into epileptic syndromes, which group certain types of seizures with other characteristic clinical aspects.
Le più importanti sindromi sono l'epilessia del lobo temporale, l'epilessia rolandica, le epilessie miocloniche dell'infanzia e dell'età giovanile, l'epilessia con assenze, la sindrome di West e la sindrome di Lennox-Gastaut. The most important syndromes are temporal lobe epilepsy, rolandic epilepsy, myoclonic epilepsies of childhood and youth, absence epilepsy, West syndrome and Lennox-Gastaut syndrome.
La farmacoterapia dell'epilessia impiega farmaci antiepilettici che con diversi meccanismi stabilizzano le proprietà elettriche della membrana delle cellule nervose, impedendo così le scariche elettriche spontanee. Pharmacotherapy of epilepsy employs antiepileptic drugs which by various mechanisms stabilize the electrical properties of the nerve cell membrane, thus preventing spontaneous electrical discharges.
Si tratta perciò di una terapia sintomatica che non elimina la causa dell'epilessia; in particolare, al momento non vi sono farmaci in grado di contrastare lo sviluppo, dopo una crisi convulsiva iniziale, di una condizione epilettica cronica. It is therefore a symptomatic therapy that does not eliminate the cause of the epilepsy; in particular, at the moment there are no drugs able to counteract the development, after an initial seizure, of a chronic epileptic condition.
La terapia deve essere scelta con cura, perché à ̈ prolungata e con effetti collaterali potenzialmente gravi. The therapy must be chosen with care, because it is prolonged and with potentially serious side effects.
La scelta del farmaco deve essere fatta considerando il tipo di crisi e la sindrome epilettica, la durata della terapia e i possibili effetti collaterali, sempre rispetto alla situazione del singolo paziente. The choice of the drug must be made considering the type of seizure and the epileptic syndrome, the duration of therapy and the possible side effects, always with respect to the situation of the individual patient.
I classici farmaci antiepilettici sono valproato e carbamazepina (che sono spesso i farmaci di prima scelta), fenitoina e fenobarbital. The classic antiepileptic drugs are valproate and carbamazepine (which are often the drugs of first choice), phenytoin and phenobarbital.
Da pochi anni à ̈ disponibile una serie di farmaci di nuova generazione (quali felbamato, gabapentin, lamotrigina, levetiracetam, oxcarbazepina, tiagabina, topiramato, vigabatrin) usati per indicazioni particolari o per aumentare l'efficacia della terapia quando la monoterapia con un antiepilettico classico non riesce a sopprimere le crisi epilettiche. A series of new generation drugs has been available for a few years (such as felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin) used for particular indications or to increase the efficacy of therapy when monotherapy with a classic antiepileptic fails to suppress seizures.
Studi clinici recenti indicano che gabapentin, lamotrigina e oxcarbazepina possono essere usati anche in monoterapia, mentre felbamato e vigabatrin comportano il rischio di effetti collaterali così seri da restringerne l'uso ad epilessie resistenti ad altri farmaci e indicazioni pediatriche particolari. Recent clinical studies indicate that gabapentin, lamotrigine and oxcarbazepine can also be used alone, while felbamate and vigabatrin carry the risk of side effects so serious that their use is restricted to epilepsies resistant to other drugs and particular pediatric indications.
L'uso di etosuccimide à ̈ ristretto alle crisi di assenza. The use of ethosuximide is restricted to absence seizures.
Per la terapia acuta di una crisi epilettica sono disponibili diazepam, lorazepam, clonazepam e fenitoina per via endovenosa o rettale. Intravenous or rectal diazepam, lorazepam, clonazepam and phenytoin are available for acute therapy of a seizure.
I farmaci antiepilettici possono interagire tra di loro e con altri farmaci con possibile variazione della loro efficacia e tossicità . Antiepileptic drugs can interact with each other and with other drugs with possible variation of their efficacy and toxicity.
Gli effetti collaterali indesiderati più frequentemente segnalati comprendono sonnolenza, senso di affaticamento, vertigini, atassia, dispnea, alterazioni gastrointestinali. The most frequently reported undesirable side effects include drowsiness, fatigue, dizziness, ataxia, dyspnoea, gastrointestinal disturbances.
Poiché l'epilessia interessa in molti casi l'età riproduttiva, la gravidanza pone questioni particolari per la farmacoterapia, in quanto nessuno dei farmaci à ̈ privo di rischio teratogeno. Since epilepsy affects reproductive age in many cases, pregnancy poses particular questions for pharmacotherapy, as none of the drugs are without teratogenic risk.
L’efficacia dei contraccettivi orali può essere ridotta dalla terapia antiepilettica a causa della accelerazione del catabolismo degli estroprogestinici da parte dei farmaci antiepilettici induttori degli enzimi epatici. In alcune forme di epilessia l’aumento di rischio per crisi nel periodo mestruale (epilessie catameniali) può rendere periodicamente insufficiente la protezione farmacologica. The efficacy of oral contraceptives can be reduced by antiepileptic therapy due to the acceleration of the catabolism of estrogen-progestins by antiepileptic drugs inducing liver enzymes. In some forms of epilepsy the increased risk of a crisis in the menstrual period (catamenial epilepsies) can periodically make pharmacological protection insufficient.
Circa il 30% delle epilessie non à ̈ sufficientemente controllato nonostante l'impiego combinato di più farmaci a dosaggi ritenuti terapeutici. In questo caso viene proposta l’asportazione chirurgica della regione cerebrale (nella maggior parte dei casi il lobo temporale medio) in cui originano le crisi epilettiche. Questa soluzione à ̈ applicabile solo quando la regione in cui originano le crisi epilettiche à ̈ ben identificabile e la sua rimozione non comporta deficit neurologici peggiorativi. About 30% of epilepsies are not sufficiently controlled despite the combined use of several drugs at dosages considered therapeutic. In this case, surgical removal of the brain region (in most cases the middle temporal lobe) where the epileptic seizures originate is proposed. This solution is applicable only when the region in which the seizures originate is clearly identifiable and its removal does not involve pejorative neurological deficits.
Pertanto sussiste tuttora la necessità di trovare nuovi composti dotati di attività anticonvulsivante, utili nel trattamento di crisi convulsive associate a varie forme di epilessia e di crisi convulsive non epilettiche dipendenti da qualsivoglia alterazione del sistema nervoso centrale. Therefore there is still the need to find new compounds with anticonvulsant activity, useful in the treatment of seizures associated with various forms of epilepsy and non-epileptic seizures dependent on any alteration of the central nervous system.
I growth hormone secretagogues (GHS) sono un gruppo di molecole sia naturali che sintetiche il cui capostipite, sintetizzato nei primi anni ’80, dimostrava una potente attività GH-secretagoga. Questi composti si sono dimostrati in grado di agire sinergicamente con il GHRH (Growth Hormone Releasing Hormone) in vivo, e in maniera additiva in vitro sulla secrezione di GH attraverso l’interazione con un recettore specifico, il GHS-R1a. Growth hormone secretagogues (GHS) are a group of both natural and synthetic molecules whose progenitor, synthesized in the early 1980s, demonstrated a powerful GH-secretagogical activity. These compounds have been shown to be able to act synergistically with the GHRH (Growth Hormone Releasing Hormone) in vivo, and in an additive manner in vitro on the secretion of GH through the interaction with a specific receptor, the GHS-R1a.
Ghrelin à ̈ un peptide endogeno di 28 aminoacidi che si lega in maniera specifica al GHS-R1a e stimola efficacemente il rilascio di GH e l’appetito. Ghrelin is an endogenous peptide of 28 amino acids that binds specifically to GHS-R1a and effectively stimulates GH release and appetite.
Oltre alla capacità di modificare la secrezione di GH, e in misura minore di prolattina e cortisolo, diversi GHS sembrano dotati di altre attività extraendocrine. Alcuni GHS dimostrano solo attività endocrine, altri solo extraendocrine, altri ancora una combinazione di alcune attività endocrine ed extraendocrine. In addition to the ability to modify GH secretion, and to a lesser extent prolactin and cortisol, several GHS seem to have other extraendocrine activities. Some GHS demonstrate only endocrine activities, others only extraendocrine, still others a combination of some endocrine and extraendocrine activities.
Sommario dell’invenzione Summary of the invention
La presente invenzione à ̈ relativa all’uso di agonisti e antagonisti dei recettori per Growth Hormone Secretagogues (GHS) per la preparazione di medicamenti utili per la prevenzione e il trattamento di convulsioni e di stati epilettici. The present invention relates to the use of agonists and antagonists of the receptors for Growth Hormone Secretagogues (GHS) for the preparation of medicaments useful for the prevention and treatment of convulsions and epileptic states.
Elenco delle figure List of figures
Figura 1 - Studio degli effetti dei GHS sull’insorgenza delle convulsioni nel ratto trattato con pilocarpina. Figure 1 - Study of the effects of GHS on the onset of convulsions in the rat treated with pilocarpine.
Figura 2 - Studio degli effetti dei GHS sulla comparsa dello stato epilettico nel ratto trattato con pilocarpina. Figure 2 - Study of the effects of GHS on the onset of status epilepticus in the rat treated with pilocarpine.
Figura 3 - Studio degli effetti dei GHS sulla mortalità del ratto trattato con pilocarpina. Figure 3 - Study of the effects of GHS on the mortality of the rat treated with pilocarpine.
Figura 4 - Studio degli effetti dei GHS sulla comparsa di crisi convulsive ricorrenti (SRSs) generalizzate o minori (parziali) nel ratto trattato con pilocarpina. Figure 4 - Study of the effects of GHS on the appearance of generalized or minor (partial) recurrent seizures (SRSs) in the rat treated with pilocarpine.
Descrizione dettagliata dell’invenzione Detailed description of the invention
La presente invenzione riguarda l’utilizzo di composti agonisti e antagonisti dei recettori dei Growth Hormone Secretagogues (GHS) per la preparazione di medicamenti in grado di inibire o bloccare le crisi convulsive e lo stato epilettico, in particolare nell’uomo. The present invention relates to the use of agonist and antagonist compounds of the Growth Hormone Secretagogues (GHS) receptors for the preparation of drugs capable of inhibiting or blocking seizures and the epileptic status, in particular in men.
Tali composti sono in grado di inibire o bloccare le crisi convulsive, ad esempio acute, ricorrenti, a grappolo (cluster), associate o non associate ad epilessia, e gli stati epilettici, come ad esempio le crisi motorie associate ad epilessia del lobo temporale (delle quali il ratto trattato con pilocarpina costituisce un modello animale validato). These compounds are able to inhibit or block seizures, for example acute, recurrent, clustered, associated or not associated with epilepsy, and epileptic states, such as motor seizures associated with temporal lobe epilepsy ( of which the pilocarpine-treated rat constitutes a validated animal model).
Gli agonisti e antagonisti dei recettori dei Growth Hormone Secretagogues (GHS) comprendono desacil ghrelin (1-28), acil ghrelin (1-27), desacil ghrelin (1-27), acil (des-Gln14) ghrelin (1-27), e desacil (des-Gln14) ghrelin (1-27), ed eventuali altri metaboliti, derivati o analoghi di ghrelin, a condizione che ghrelin sia escluso. Growth Hormone Secretagogues (GHS) receptor agonists and antagonists include desacyl ghrelin (1-28), acyl ghrelin (1-27), desacyl ghrelin (1-27), acyl (des-Gln14) ghrelin (1-27) , and desacyl (des-Gln14) ghrelin (1-27), and any other metabolites, derivatives or analogues of ghrelin, provided that ghrelin is excluded.
L’invenzione à ̈ relativa all’utilizzo di peptidi, pseudopeptidi (peptoidi), composti peptidomimetici, derivati peptidici o composti non peptidici ad attività agonista, agonista parziale o antagonista dei recettori dei GHS. The invention relates to the use of peptides, pseudopeptides (peptoids), peptidomimetic compounds, peptide derivatives or non-peptide compounds with agonist activity, partial agonist or antagonist of GHS receptors.
Esempi di composti che possono essere usati secondo la presente invenzione sono l’esapeptide EP80317, hexarelin e suoi analoghi, rispettivamente descritti in WO 91/18016, WO 96/10040, WO 01/96300, WO 02/08250 e WO 03/004518. Examples of compounds that can be used according to the present invention are hexapeptide EP80317, hexarelin and its analogues, respectively described in WO 91/18016, WO 96/10040, WO 01/96300, WO 02/08250 and WO 03/004518 .
Antagonisti non peptidici di ghrelin utilizzabili sono descritti in WO 2005/30734. Usable non-peptide ghrelin antagonists are disclosed in WO 2005/30734.
Esempi di GHS di tipo peptidomimetico sono descritti in Examples of peptidomimetic-type GHS are described in
WO 96/15148, mentre pseudopeptidi sono noti da WO 2005/105828. WO 96/15148, while pseudopeptides are known from WO 2005/105828.
Inoltre, sono particolarmente preferiti EP80317, hexarelin e suoi Furthermore, EP80317, hexarelin and its are particularly preferred
derivati o analoghi (in particolare quelli contrassegnati dai codici EP71563, derivatives or similar (in particular those marked by the codes EP71563,
EP70905, EP70555, EP80279, EP80874, EP255, EP256, EP71180, EP80089, EP70905, EP70555, EP80279, EP80874, EP255, EP256, EP71180, EP80089,
EP70760, EP92440, EP930497). EP70760, EP92440, EP930497).
La struttura e la sequenza di alcuni derivati o analoghi sopra citati sono The structure and sequence of some derivatives or analogues mentioned above are
riportate in Tabella. Le sequenze riportate in Tabella sono identificate shown in the Table. The sequences reported in the Table are identified
nell’allegata lista delle sequenze, a cui si fa riferimento (SEQ. ID No:). in the attached list of sequences, to which reference is made (SEQ. ID No :).
Codice Formula di struttura del composto SEQ ID No: EP71563 Cys-Tyr-GAB-D-Mrp-D-Mrp-Lys-NH2 SEQ ID No: 1 EP80317 Haic-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2 SEQ ID No: 2 EP70905 S,S_Spiro_Pro_Leu_-D-2Me-Trp-dLys-Trp-dPhe-Lys-NH2 SEQ ID No: 3 EP70555 GAB-D-Trp(2Me)-D-Trp(2Me)-D-Trp(2Me)-Arg(NO2)-NH2 SEQ ID No: 4 EP80279 Tyr-S_S_Spiro_Pro_Leu-D-2Me-Trp-dLys-Trp-dPhe-Lys-NH2 SEQ ID No: 5 EP80874 D-Mrp-D-Cys-Pal3-D-Trp-Lys-Val-Cys-Mrp-NH2 SEQ ID No: 6 EP255 Pipecolil-D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2 SEQ ID No: 7 EP256 D- Pipecolil-D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2 SEQ ID No: 8 EP71180 Aib-D-2Me-Trp-dTpi-NH2 SEQ ID No: 9 EP80089 Ser-Arg-Asp-Val-Tyr(PO3H2)-Glu-Glu-Asp-Ser-Tyr-Val-Lys- SEQ ID No: 10 Code Compound Structural Formula SEQ ID No: EP71563 Cys-Tyr-GAB-D-Mrp-D-Mrp-Lys-NH2 SEQ ID No: 1 EP80317 Haic-D-Mrp-D-Lys-Trp-D-Phe- Lys-NH2 SEQ ID No: 2 EP70905 S, S_Spiro_Pro_Leu_-D-2Me-Trp-dLys-Trp-dPhe-Lys-NH2 SEQ ID No: 3 EP70555 GAB-D-Trp (2Me) -D-Trp (2Me) - D-Trp (2Me) -Arg (NO2) -NH2 SEQ ID No: 4 EP80279 Tyr-S_S_Spiro_Pro_Leu-D-2Me-Trp-dLys-Trp-dPhe-Lys-NH2 SEQ ID No: 5 EP80874 D-Mrp-D- Cys-Pal3-D-Trp-Lys-Val-Cys-Mrp-NH2 SEQ ID No: 6 EP255 Pipecolil-D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2 SEQ ID No: 7 EP256 D- Pipecolil- D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2 SEQ ID No: 8 EP71180 Aib-D-2Me-Trp-dTpi-NH2 SEQ ID No: 9 EP80089 Ser-Arg-Asp-Val-Tyr (PO3H2) -Glu-Glu-Asp-Ser-Tyr-Val-Lys- SEQ ID No: 10
Arg-NH2 Arg-NH2
EP70760 S,S_Spiro_Pro_Leu-D-2Me-Trp-Ala-Trp-dPhe-Lys-NH2 SEQ ID No: 11 EP92440 His-Ala-D-Trp-D-Lys-2Me-Trp-DPhe-Lys-NH2 SEQ ID No: 12 EP930497 Tyr-Ala-His-DTrp(2Me)-Ala-Trp-DPhe-Lys-NH2 SEQ ID No: 13 JMV1843 H-Aib-(D)-Trp-(D)-gTrp-formil SEQ ID No: 14 JMV2959 (R)-N-(1-(4-(4-Metossibenzil)-5-fenetil-4H-1,2,4-triazol-3-il)-2-(1H-indol-3-il)etil)-2-aminoacetamide EP70760 S, S_Spiro_Pro_Leu-D-2Me-Trp-Ala-Trp-dPhe-Lys-NH2 SEQ ID No: 11 EP92440 His-Ala-D-Trp-D-Lys-2Me-Trp-DPhe-Lys-NH2 SEQ ID No : 12 EP930497 Tyr-Ala-His-DTrp (2Me) -Ala-Trp-DPhe-Lys-NH2 SEQ ID No: 13 JMV1843 H-Aib- (D) -Trp- (D) -gTrp-formil SEQ ID No: 14 JMV2959 (R) -N- (1- (4- (4-Methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide
Acil ghrelin Gly - Ser - Ser (O - n - Octanoil) - Phe - Leu - Ser - Pro - Glu - SEQ ID No: 15 (1-27) His - Gln - Arg - Val - Gln - Gln - Arg - Lys - Glu - Ser - Lys -Lys - Pro - Pro - Ala - Lys - Leu - Gln – Pro Acil ghrelin Gly - Ser - Ser (O - n - Octanoil) - Phe - Leu - Ser - Pro - Glu - SEQ ID No: 15 (1-27) His - Gln - Arg - Val - Gln - Gln - Arg - Lys - Glu - Ser - Lys -Lys - Pro - Pro - Ala - Lys - Leu - Gln - Pro
Desacil ghrelin Gly - Ser - Ser - Phe - Leu - Ser - Pro - Glu - His - Gln - Arg - SEQ ID No: 16 (1-27) Val - Gln - Gln - Arg - Lys - Glu - Ser - Lys - Lys - Pro - Pro -Ala - Lys - Leu - Gln – Pro Desacil ghrelin Gly - Ser - Ser - Phe - Leu - Ser - Pro - Glu - His - Gln - Arg - SEQ ID No: 16 (1-27) Val - Gln - Gln - Arg - Lys - Glu - Ser - Lys - Lys - Pro - Pro -Ala - Lys - Leu - Gln - Pro
Acil (des- Gly - Ser - Ser(O - n - Octanoil) - Phe - Leu - Ser - Pro - Glu - SEQ ID No: 17 Gln14) ghrelin His - Gln - Lys - Ala - Gln - Arg - Lys - Glu - Ser - Lys - Lys -(1-27) Pro - Pro - Ala - Lys - Leu - Gln - Pro – Arg Acil (des- Gly - Ser - Ser (O - n - Octanoil) - Phe - Leu - Ser - Pro - Glu - SEQ ID No: 17 Gln14) ghrelin His - Gln - Lys - Ala - Gln - Arg - Lys - Glu - Ser - Lys - Lys - (1-27) Pro - Pro - Ala - Lys - Leu - Gln - Pro - Arg
Desacil (des- Gly - Ser - Ser- Phe - Leu - Ser - Pro - Glu - His - Gln - Lys - SEQ ID No: 18 Gln14) ghrelin Ala - Gln - Arg - Lys - Glu - Ser - Lys - Lys - Pro - Pro - Ala -(1-27) Lys - Leu - Gln - Pro – Arg Desacil (des- Gly - Ser - Ser- Phe - Leu - Ser - Pro - Glu - His - Gln - Lys - SEQ ID No: 18 Gln14) ghrelin Ala - Gln - Arg - Lys - Glu - Ser - Lys - Lys - Pro - Pro - Ala - (1-27) Lys - Leu - Gln - Pro - Arg
Desacil ghrelin Gly - Ser – Ser - Phe - Leu - Ser - Pro - Glu - His - Gln - Arg - SEQ ID No: 19 (1-28) Val - Gln - Gln - Arg - Lys - Glu - Ser - Lys - Lys - Pro - Pro -Ala - Lys - Leu - Gln - Pro - Arg Desacil ghrelin Gly - Ser - Ser - Phe - Leu - Ser - Pro - Glu - His - Gln - Arg - SEQ ID No: 19 (1-28) Val - Gln - Gln - Arg - Lys - Glu - Ser - Lys - Lys - Pro - Pro -Ala - Lys - Leu - Gln - Pro - Arg
Tabella Table
Secondo un aspetto dell’invenzione, i composti possono essere utilizzati in forma di sali, esteri, solvati. According to one aspect of the invention, the compounds can be used in the form of salts, esters, solvates.
Secondo un ulteriore aspetto dell’invenzione, tali composti possono essere somministrati sia da soli che in associazione con altri composti, quali ad esempio anticonvulsivanti o antiepilettici, compresi i loro sali e i loro esteri. According to a further aspect of the invention, these compounds can be administered either alone or in association with other compounds, such as anticonvulsants or antiepileptics, including their salts and esters.
Inoltre, l’invenzione riguarda l’uso dei composti sia da soli che in associazione con almeno un altro composto anticonvulsivante o antiepilettico, per la preparazione di medicamenti in grado di inibire o bloccare le crisi convulsive, quali ad esempio quelle acute, ricorrenti, a grappolo, e lo stato epilettico, in particolare nell’uomo. Furthermore, the invention relates to the use of the compounds both alone and in association with at least one other anticonvulsant or antiepileptic compound, for the preparation of drugs capable of inhibiting or blocking seizures, such as acute, recurrent , cluster, and status epilepticus, particularly in humans.
Secondo un aspetto preferito dell’invenzione, i composti anticonvulsivanti o antiepilettici possono essere scelti tra diazepam, lorazepam, midazolam, clonazepam, clorazepato, fenobarbital, metilfenobarbital, hexibarbital, fenitoina, mefenitoina, etotoina, fosfenitoina, trimetadione, fensuccimide, etosuccimide, carbamazepina, primidone, acido valproico, oxcarbazepina, felbamato, gabapentin, lamotrigina, levetiracetam, brivaracetam, lacosamide, tiagabina, zonisamide, topiramato, fenacetamide, vigabatrin, loro sali e loro esteri. According to a preferred aspect of the invention, the anticonvulsant or antiepileptic compounds can be selected from diazepam, lorazepam, midazolam, clonazepam, clorazepate, phenobarbital, methylphenobarbital, hexibarbital, phenytoin, mephenytoin, ethotoin, fosphenytoine, trimetadide, fensimephate primidone, valproic acid, oxcarbazepine, felbamate, gabapentin, lamotrigine, levetiracetam, brivaracetam, lacosamide, tiagabine, zonisamide, topiramate, phenacetamide, vigabatrin, their salts and their esters.
Secondo un aspetto dell’invenzione, i composti e le associazioni farmacologiche possono essere utilizzati per trattare una o più condizioni cliniche patologiche comprese nel gruppo delle convulsioni acute, convulsioni ricorrenti, convulsioni a grappolo (cluster), e dello stato epilettico in soggetti che necessitino di tale trattamento. According to one aspect of the invention, the compounds and pharmacological associations can be used to treat one or more pathological clinical conditions including in the group of acute convulsions, recurrent convulsions, cluster convulsions, and status epilepticus in subjects requiring of this treatment.
Il termine “trattamento†viene utilizzato con il significato di prevenire, ridurre il rischio e/o ritardare l’insorgenza, alleviare, eradicare le patologie oggetto del trattamento. The term â € œtreatmentâ € is used with the meaning of preventing, reducing the risk and / or delaying the onset, alleviating, eradicating the pathologies being treated.
Secondo un aspetto preferito, i composti e le associazioni farmacologiche descritte nell’invenzione possono essere utilizzate per prevenire o interrompere le convulsioni acute, le convulsioni ripetute, le convulsioni a grappolo e/o lo stato epilettico e, eventualmente, per prevenire l’insorgenza di ulteriori convulsioni successive. According to a preferred aspect, the compounds and the pharmacological associations described in the invention can be used to prevent or stop acute convulsions, repeated convulsions, cluster convulsions and / or status epilepticus and, possibly, to prevent seizures. onset of further subsequent seizures.
Tali medicamenti possono essere vantaggiosamente impiegati, ad esempio da soli o in associazioni terapeutiche, per la prevenzione e il trattamento delle convulsioni e delle crisi epilettiche in particolare in gravidanza, nei casi di farmacoresistenza ai farmaci anticonvulsivanti e antiepilettici attualmente in terapia, oppure quando gli effetti collaterali di un farmaco utilizzato in terapia ne precludono la somministrazione a lungo termine. These medicaments can be advantageously used, for example alone or in therapeutic combinations, for the prevention and treatment of convulsions and epileptic seizures in particular during pregnancy, in cases of drug resistance to anticonvulsant and antiepileptic drugs currently under therapy, or when the effects collaterals of a drug used in therapy preclude its long-term administration.
Gli agonisti e antagonisti del recettore GHS sono tipicamente somministrati per via orale o parenterale, a seconda delle caratteristiche farmacocinetiche di ogni singolo specifico composto. Le dosi terapeutiche efficaci potranno essere determinate da esperti del settore in base ai dati di farmacocinetica, farmacodinamica e tossicologia. Tali dosi potranno essere uguali, inferiori o superiori a quelle già note o in studio per le indicazioni note dei composti agonisti e antagonisti dei recettori per i GHS. Si presume che in linea di massima le dosi efficaci saranno quanto meno dello stesso ordine di grandezza di quelle per le indicazioni tradizionali. GHS receptor agonists and antagonists are typically administered orally or parenterally, depending on the pharmacokinetic characteristics of each specific compound. The effective therapeutic doses can be determined by experts in the field on the basis of pharmacokinetic, pharmacodynamic and toxicology data. These doses may be equal, lower or higher than those already known or under study for the known indications of the agonist and antagonist compounds of the receptors for the GHS. It is assumed that in principle effective doses will be at least of the same order of magnitude as those for traditional indications.
Gli esempi di seguito riportati illustrano ulteriormente, ma non in modo limitativo, l’invenzione. The following examples illustrate further, but not in a limiting way, the invention.
Esempi Examples
L’esperimento à ̈ stato condotto su ratti maschi adulti Sprague-Dawley (Harlan, S. Pietro al Natisone, Italia) del peso compreso tra 225-250 grammi (con un tempo di ambientamento in stabulario di almeno 4 giorni). The experiment was conducted on adult male Sprague-Dawley rats (Harlan, S. Pietro al Natisone, Italy) weighing between 225-250 grams (with an acclimatization time of at least 4 days).
Il gruppo degli animali controllo (n=16) Ã ̈ stato trattato con iniezione intraperitoneale (i.p.) di pilocarpina (380 mg/Kg). Al fine di prevenire i disagi indotti dalla stimolazione dei recettori periferici muscarinici, i ratti hanno subito un pretrattamento con scopolamina metilnitrato per via sottocutanea (s.c.) (1 mg/Kg) 30 minuti prima della somministrazione del convulsivante. The group of control animals (n = 16) was treated with intraperitoneal (i.p.) injection of pilocarpine (380 mg / kg). In order to prevent the discomfort induced by the stimulation of peripheral muscarinic receptors, the rats underwent pretreatment with subcutaneous (SC) scopolamine methylnitrate (1 mg / kg) 30 minutes before administration of the convulsant.
Il protocollo a cui à ̈ stato sottoposto il gruppo degli animali trattati con farmaci (n=37) prevede il pretrattamento con scopolamina metilnitrato seguito dopo 20 minuti dalla somministrazione i.p. del farmaco e dopo ulteriori 10 minuti di pilocarpina i.p. (380 mg/Kg). The protocol to which the group of animals treated with drugs was subjected (n = 37) provides for the pretreatment with scopolamine methylnitrate followed 20 minutes after i.p. administration. of the drug and after an additional 10 minutes of pilocarpine i.p. (380 mg / Kg).
Altri gruppi di ratti sono stati trattati i.p. con 1,5 mg/Kg ghrelin (n=4), 1,5 mg/Kg desacil ghrelin (n=5), 320 µg/Kg hexarelin (n=8), 320 µg/Kg JMV1843 (H-Aib-(D)-Trp-(D)-gTrp-formil) (n=4), 320 µg/Kg JMV2959 ((R)-N-(1-(4-(4-Metossibenzil)-5-fenetil-4H-1,2,4-triazol-3-il)-2-(1H-indol-3-il)etil)-2-aminoacetamide) (n=6) e 320 µg/Kg EP80317 (n=10). Other groups of rats were treated i.p. with 1.5 mg / Kg ghrelin (n = 4), 1.5 mg / Kg desacil ghrelin (n = 5), 320 µg / Kg hexarelin (n = 8), 320 µg / Kg JMV1843 (H-Aib- ( D) -Trp- (D) -gTrp-formyl) (n = 4), 320 µg / Kg JMV2959 ((R) -N- (1- (4- (4-Methoxybenzyl) -5-phenethyl-4H-1 , 2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide) (n = 6) and 320 µg / Kg EP80317 (n = 10).
Un gruppo di ratti à ̈ stato trattato con 1,5 mg/Kg di EP80317 immediatamente dopo la comparsa della prima crisi convulsiva (n = 5). One group of rats was treated with 1.5 mg / kg of EP80317 immediately after the onset of the first seizure (n = 5).
In tutti gli animali (n=34), lo stato epilettico indotto dalla somministrazione di pilocarpina à ̈ stato bloccato dopo 20-40 minuti dall’insorgenza della prima crisi epilettica mediante la somministrazione i.p. di diazepam (20 mg/Kg). Gli animali che non hanno sviluppato crisi epilettiche hanno ricevuto diazepam 60 minuti dopo l’iniezione della pilocarpina. In all animals (n = 34), the status epilepticus induced by the administration of pilocarpine was blocked 20-40 minutes after the onset of the first seizure by i.p. of diazepam (20 mg / kg). Animals that did not develop seizures received diazepam 60 minutes after pilocarpine injection.
Gli animali sono stati monitorati valutando i seguenti parametri: The animals were monitored by evaluating the following parameters:
- Latenza della prima crisi (periodo tra l’iniezione di pilocarpina e l’insorgenza della prima crisi, espressa in minuti) - Latency of the first seizure (period between the pilocarpine injection and the onset of the first seizure, expressed in minutes)
- Latenza dello Stato Epilettico (SE) (periodo tra la prima crisi e l’instaurarsi di crisi ininterrotte, espressa in minuti) - Latency of the State Epilepticus (SE) (period between the first seizure and the onset of uninterrupted seizures, expressed in minutes)
- Durata SE (periodo tra l’instaurarsi dello SE e la somministrazione di diazepam, espressa in minuti) - SE duration (period between the onset of the SE and the administration of diazepam, expressed in minutes)
- Risposta al diazepam (espressa in minuti) - Response to diazepam (expressed in minutes)
- Recupero dal coma - Recovery from coma
- Mortalità (%) - Mortality (%)
- Recupero (%) - Recovery (%)
- Presenza di lesioni macroscopiche (%) - Presence of macroscopic lesions (%)
- Risposta alla pilocarpina (%) - Pilocarpine response (%)
- Induzione dello SE (%) - SE induction (%)
- Comparsa di crisi convulsive ricorrenti generalizzate o parziali, valutate secondo la scala di Racine (%) - Appearance of generalized or partial recurrent seizures, evaluated according to the Racine scale (%)
Esempio 1: Studio degli effetti dei GHS sull’insorgenza delle convulsioni nel ratto trattato con pilocarpina Example 1: Study of the effects of GHS on the onset of seizures in the rat treated with pilocarpine
I risultati di questo esperimento, riportati nell’allegata Figura 1, dimostrano che alcuni GHS sono in grado di inibire in vivo l’insorgenza delle convulsioni in seguito alla somministrazione di pilocarpina. I dati sono espressi in % degli animali sottoposti a trattamento farmacologico. Tale effetto à ̈ particolarmente pronunciato con EP80317, raggiungendo il 50% di inibizione dell’insorgenza di convulsioni. La specificità dell’azione di questi GHS à ̈ dimostrata dal fatto che un effetto parziale à ̈ stato misurato anche con desacil ghrelin, hexarelin e JMV1843, mentre ghrelin e JMV2959 sono risultati inattivi su questo parametro. The results of this experiment, reported in the attached Figure 1, show that some GHS are able to inhibit the onset of convulsions in vivo following the administration of pilocarpine. The data are expressed in% of animals subjected to pharmacological treatment. This effect is particularly pronounced with EP80317, reaching 50% inhibition of the onset of seizures. The specificity of the action of these GHS is demonstrated by the fact that a partial effect was also measured with desacil ghrelin, hexarelin and JMV1843, while ghrelin and JMV2959 were found to be inactive on this parameter.
Esempio 2: Studio degli effetti dei GHS sulla comparsa dello stato epilettico nel ratto trattato con pilocarpina Example 2: Study of the effects of GHS on the onset of status epilepticus in the rat treated with pilocarpine
I risultati di questo studio, riportati nell’allegata Figura 2, hanno permesso di evidenziare che EP80317 previene l’insorgenza dello stato epilettico nel 60% dei ratti trattati con pilocarpina. I dati sono espressi in % degli animali sottoposti a trattamento farmacologico. Anche desacil ghrelin e hexarelin dimostravano una attività interessante, essendo efficaci nel prevenire lo stato epilettico, rispettivamente nel 60% e nel 50% degli animali. L’effetto di JMV1843 à ̈ risultato più modesto, mentre anche su questo parametro ghrelin e JMV2959 si sono dimostrati inefficaci. The results of this study, reported in the attached Figure 2, made it possible to highlight that EP80317 prevents the onset of status epilepticus in 60% of rats treated with pilocarpine. The data are expressed in% of animals subjected to pharmacological treatment. Desacil ghrelin and hexarelin also showed interesting activity, being effective in preventing status epilepticus in 60% and 50% of animals, respectively. The effect of JMV1843 was more modest, while also on this parameter ghrelin and JMV2959 proved ineffective.
Esempio 3: Studio degli effetti dei GHS sulla mortalità del ratto trattato con pilocarpina Example 3: Study of the effects of GHS on the mortality of the rat treated with pilocarpine
I risultati di questo studio, riportati nell’allegata Figura 3, hanno permesso di evidenziare che, mentre nel gruppo di controllo la mortalità raggiungeva il 50% dei ratti trattati con pilocarpina, il trattamento con ghrelin, desacil ghrelin, hexarelin, EP80317 e JMV1843 permetteva la sopravvivenza del 100% degli animali trattati. I dati sono espressi in % degli animali sottoposti a trattamento farmacologico. Anche in questo caso il trattamento con JMV2959 si dimostrava scarsamente o per nulla efficace. The results of this study, reported in the attached Figure 3, made it possible to highlight that, while in the control group the mortality reached 50% of rats treated with pilocarpine, treatment with ghrelin, desacil ghrelin, hexarelin, EP80317 and JMV1843 allowed the survival of 100% of the treated animals. The data are expressed in% of animals subjected to pharmacological treatment. Also in this case the treatment with JMV2959 proved to be scarcely or not at all effective.
Esempio 4: Studio degli effetti dei GHS sulla comparsa di crisi convulsive ricorrenti generalizzate o minori nel ratto trattato con pilocarpina Si à ̈ studiato l’effetto, in particolare di EP80317, sulla epilettogenesi (comparsa di crisi convulsive spontanee generalizzate, stadio V della scala di Racine, o parziali, stadio I-IV della stessa scala) nel ratto trattato con pilocarpina. I dati sono espressi in % degli animali sottoposti a trattamento farmacologico. Example 4: Study of the effects of GHS on the appearance of generalized or minor recurrent seizures in the rat treated with pilocarpine The effect, in particular of EP80317, on epileptogenesis was studied (appearance of generalized spontaneous seizures, stage V of the scale of Racine, or partial, stage I-IV of the same scale) in the rat treated with pilocarpine. The data are expressed in% of animals subjected to pharmacological treatment.
I risultati di questo studio, condotto per un periodo di tre settimane, sono riportati nell’allegata Figura 4 e hanno permesso di evidenziare che, mentre nel gruppo di controllo le crisi convulsive generalizzate ricorrenti sono comparse nel 70% dei ratti trattati con pilocarpina, il trattamento con EP80317 effettuato immediatamente dopo la comparsa della prima crisi convulsiva ha limitato i fenomeni epilettogeni nel 100% degli animali trattati. Nei ratti trattati con EP80317 non sono state osservate crisi o sono state registrate solo crisi non ricorrenti. The results of this study, carried out over a period of three weeks, are shown in the attached Figure 4 and made it possible to highlight that, while in the control group recurrent generalized seizures appeared in 70% of the rats treated with pilocarpine, treatment with EP80317 carried out immediately after the onset of the first seizure limited the epileptogenic phenomena in 100% of the treated animals. In rats treated with EP80317 no seizures were observed or only non-recurrent seizures were recorded.
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LISTA DELLE SEQUENZE LIST OF SEQUENCES
<110> Università degli Studi di Milano-Bicocca <110> University of Milan-Bicocca
Università degli Studi di Modena e Reggio Emilia University of Modena and Reggio Emilia
<120> Uso di agonisti e antagonisti dei recettori per i Growth Hormone Secretagogues per la prevenzione e il trattamento di convulsioni ed epilessia <120> Use of Secretagogues Growth Hormone Receptor Agonists and Antagonists for the Prevention and Treatment of Seizures and Epilepsy
<130> 8975M <130> 8975M
<160> 19 <160> 19
<170> PatentIn version 3.3 <170> PatentIn version 3.3
<210> 1 <210> 1
<211> 6 <211> 6
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ acido gamma-amino-butirrico <223> Xaa is gamma-amino-butyric acid
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (4)..(5) <222> (4) .. (5)
<223> Xaa à ̈ D-2-metil-Trp <223> Xaa is D-2-methyl-Trp
<400> 1 <400> 1
Cys Tyr Xaa Xaa Xaa Lys Cys Tyr Xaa Xaa Xaa Lys
1 5 1 5
<210> 2 <210> 2
<211> 6 <211> 6
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ Haic <223> Xaa is Haic
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ D-2-metil-Trp <223> Xaa is D-2-methyl-Trp
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ D-Lys <223> Xaa is D-Lys
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 2 <400> 2
Xaa Xaa Xaa Trp Xaa Lys Xaa Xaa Xaa Trp Xaa Lys
1 5 1 5
<210> 3 <210> 3
<211> 7 <211> 7
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ S,S-Spiro-Pro <223> Xaa à ̈ S, S-Spiro-Pro
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (4)..(4) <222> (4) .. (4)
<223> Xaa à ̈ D-Lys <223> Xaa is D-Lys
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (6)..(6) <222> (6) .. (6)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 3 <400> 3
Xaa Leu Xaa Xaa Trp Xaa Lys 1 5 Xaa Leu Xaa Xaa Trp Xaa Lys 1 5
<210> 4 <210> 4
<211> 5 <211> 5
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ GAB <223> Xaa is GAB
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(4) <222> (2) .. (4)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ Arg(NO2) <223> Xaa à ̈ Arg (NO2)
<400> 4 <400> 4
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 1 5
<210> 5 <210> 5
<211> 8 <211> 8
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ S,S-Spiro-Pro <220> <223> Xaa à ̈ S, S-Spiro-Pro <220>
<221> MOD_RES <221> MOD_RES
<222> (4)..(4) <222> (4) .. (4)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ D-Lys <223> Xaa is D-Lys
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (7)..(7) <222> (7) .. (7)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 5 <400> 5
Tyr Xaa Leu Xaa Xaa Trp Xaa Lys 1 5 Tyr Xaa Leu Xaa Xaa Trp Xaa Lys 1 5
<210> 6 <210> 6
<211> 8 <211> 8
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ D-2-metil-Trp <221> MOD_RES <223> Xaa is D-2-methyl-Trp <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ D-Cys <223> Xaa is D-Cys
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ Pal3 <223> Xaa is Pal3
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (4)..(4) <222> (4) .. (4)
<223> Xaa à ̈ D-Trp <223> Xaa is D-Trp
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (8)..(8) <222> (8) .. (8)
<223> Xaa à ̈ 2-metil-Trp <400> 6 <223> Xaa is 2-methyl-Trp <400> 6
Xaa Xaa Xaa Xaa Lys Val Cys Xaa 1 5 Xaa Xaa Xaa Xaa Lys Val Cys Xaa 1 5
<210> 7 <210> 7
<211> 6 <211> 6
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ Pip <223> Xaa is Pip
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 7 <400> 7
Xaa Xaa Ala Trp Xaa Lys Xaa Xaa Ala Trp Xaa Lys
1 5 1 5
<210> 8 <210> 8
<211> 6 <211> 6
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <221> MOD_RES <223> Synthetic peptide <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ D-Pip <223> Xaa is D-Pip
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 8 <400> 8
Xaa Xaa Ala Trp Xaa Lys 1 5 Xaa Xaa Ala Trp Xaa Lys 1 5
<210> 9 <210> 9
<211> 3 <211> 3
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ Aib <223> Xaa is Aib
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ D-Tpi <223> Xaa is D-Tpi
<400> 9 <400> 9
Xaa Xaa Xaa Xaa Xaa Xaa
1 1
<210> 10 <210> 10
<211> 13 <211> 13
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ Tyr(PO3H2) <223> Xaa à ̈ Tyr (PO3H2)
<400> 10 <400> 10
Ser Arg Asp Val Xaa Glu Glu Asp Ser Tyr Val Lys Arg 1 5 10 Ser Arg Asp Val Xaa Glu Glu Asp Ser Tyr Val Lys Arg 1 5 10
<210> 11 <210> 11
<211> 7 <211> 7
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ S,S-Spiro-Pro <223> Xaa à ̈ S, S-Spiro-Pro
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ D-2-metil-Trp <223> Xaa is D-2-methyl-Trp
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (6)..(6) <222> (6) .. (6)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 11 <400> 11
Xaa Leu Xaa Ala Trp Xaa Lys Xaa Leu Xaa Ala Trp Xaa Lys
1 5 1 5
<210> 12 <210> 12
<211> 7 <211> 7
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ D-Trp <223> Xaa is D-Trp
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (4)..(4) <222> (4) .. (4)
<223> Xaa à ̈ D-Lys <223> Xaa is D-Lys
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (5)..(5) <222> (5) .. (5)
<223> Xaa à ̈ 2-metil-Trp <223> Xaa is 2-methyl-Trp
<221> MOD_RES <221> MOD_RES
<222> (6)..(6) <222> (6) .. (6)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 12 <400> 12
His Ala Xaa Xaa Xaa Xaa Lys His Ala Xaa Xaa Xaa Xaa Lys
1 5 1 5
<210> 13 <210> 13
<211> 8 <211> 8
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (4)..(4) <222> (4) .. (4)
<223> Xaa à ̈ D-2-metil-Trp <220> <223> Xaa is D-2-methyl-Trp <220>
<221> MOD_RES <221> MOD_RES
<222> (7)..(7) <222> (7) .. (7)
<223> Xaa à ̈ D-Phe <223> Xaa is D-Phe
<400> 13 <400> 13
Tyr Ala His Xaa Ala Trp Xaa Lys 1 5 Tyr Ala His Xaa Ala Trp Xaa Lys 1 5
<210> 14 <210> 14
<211> 3 <211> 3
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (1)..(1) <222> (1) .. (1)
<223> Xaa à ̈ H-Aib <223> Xaa is H-Aib
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (2)..(2) <222> (2) .. (2)
<223> Xaa à ̈ D-Trp <223> Xaa is D-Trp
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ D-gTrp-formil <400> 14 <223> Xaa à ̈ D-gTrp-formil <400> 14
Xaa Xaa Xaa Xaa Xaa Xaa
1 1
<211> 27 <211> 27
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ Ser(O-n-Octanoil) <223> Xaa à ̈ Ser (O-n-Octanoil)
<400> 15 <400> 15
Gly Ser Xaa Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15 Gly Ser Xaa Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15
Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro
20 25 20 25
<210> 16 <210> 16
<211> 27 <211> 27
<212> PRT <212> PRT
<213> Homo sapiens <213> Homo sapiens
<400> 16 <400> 16
Gly Ser Ser Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15 Gly Ser Ser Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15
Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro
20 25 20 25
<210> 17 <210> 17
<211> 27 <211> 27
<212> PRT <212> PRT
<213> Artificiale <213> Artificial
<220> <220>
<223> Peptide sintetico <223> Synthetic peptide
<220> <220>
<221> MOD_RES <221> MOD_RES
<222> (3)..(3) <222> (3) .. (3)
<223> Xaa à ̈ Ser(O-n-Octanoil) <223> Xaa à ̈ Ser (O-n-Octanoil)
<400> 17 <400> 17
Gly Ser Xaa Phe Leu Ser Pro Glu His Gln Lys Ala Gln Arg Lys Glu 1 5 10 15 Gly Ser Xaa Phe Leu Ser Pro Glu His Gln Lys Ala Gln Arg Lys Glu 1 5 10 15
Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg
<211> 27 <211> 27
<212> PRT <212> PRT
<213> Homo sapiens <213> Homo sapiens
<400> 18 <400> 18
Gly Ser Ser Phe Leu Ser Pro Glu His Gln Lys Ala Gln Arg Lys Glu 1 5 10 15 Gly Ser Ser Phe Leu Ser Pro Glu His Gln Lys Ala Gln Arg Lys Glu 1 5 10 15
Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg
20 25 20 25
<210> 19 <210> 19
<211> 28 <211> 28
<212> PRT <212> PRT
<213> Homo sapiens <213> Homo sapiens
<400> 19 <400> 19
Gly Ser Ser Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15 Gly Ser Ser Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15
Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg
20 25 20 25
Claims (7)
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Citations (2)
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|---|---|---|---|---|
| WO2000029011A1 (en) * | 1998-11-16 | 2000-05-25 | Zentaris Ag | Treatment of tumors by administration of growth hormone releasing compounds and their antagonists |
| WO2004017986A1 (en) * | 2002-08-23 | 2004-03-04 | Valorisation-Recherche, Societe En Commandite | Growth hormone-releasing peptides in the treatment of prevention of atherosclerosis and hypercholesterolemia |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000029011A1 (en) * | 1998-11-16 | 2000-05-25 | Zentaris Ag | Treatment of tumors by administration of growth hormone releasing compounds and their antagonists |
| WO2004017986A1 (en) * | 2002-08-23 | 2004-03-04 | Valorisation-Recherche, Societe En Commandite | Growth hormone-releasing peptides in the treatment of prevention of atherosclerosis and hypercholesterolemia |
| US20060241054A1 (en) * | 2002-08-23 | 2006-10-26 | Huy Ong | Growth hormone-releasing peptides in the treatment of prevention of atherosclerosis and hypercholesterolemia |
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| Title |
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| BULGARELLI I ET AL: "Desacyl-ghrelin and synthetic GH-secretagogues modulate the production of inflammatory cytokines in mouse microglia cells stimulated by [beta]-amyloid fibrils", JOURNAL OF NEUROSCIENCE RESEARCH 2009 WILEY-LISS INC. USA LNKD- DOI:10.1002/JNR.22088, vol. 87, no. 12, September 2009 (2009-09-01), pages 2718 - 2727, XP002592026 * |
| KAMINSKI R M ET AL: "Benefit of combination therapy in epilepsy: A review of the preclinical evidence with levetiracetam", EPILEPSIA 200903 US LNKD- DOI:10.1111/J.1528-1167.2008.01713.X, vol. 50, no. 3, March 2009 (2009-03-01), pages 387 - 397, XP002592126 * |
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