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Definitions

• the present invention relates to novel peptides including novel antiarrhythmic peptides of linear or cyclic structure having improved stability in vitro and/or in vivo, to compositions comprising said peptides, and to uses of said peptides for the preparation of medicaments.
• Sudden death due to cardiac arrhythmias is one of the leading causes of death in the Western world.
• the most common disease responsible for sudden death is ischemic heart disease but in younger subjects inherited diseases such as hypertrophic cardiomyopathy and long QT syndrome are also important.
• Cardiac arrhythmias may arise from abnormalities in impulse formation, impulse conduction, or a combination of both.
• the regulation of impulse formation and conduction involves a complex interaction between the autonomic nervous system, cardiac ion channels, and cardiac gap junctions.
• the results of pharmacological prevention of especially ischemia-induced arrhythmias have been disappointing.
• clinical trials have documented that several class I and class III antiarrhythmic drugs increase mortality in patients with ischemic heart disease [1] .
• a common feature of all antiarrhythmic drugs presently in use is that they interfere with either cardiac ion channels (sodium, potassium, and calcium channels) or the autonomic nervous system, thereby interfering with the generation of the action potential.
• antiarrhythmic drugs are flecainide, encainide, moricizine, and quinidine.
• Antiarrhythmic drugs that lengthen cardiac repolarization such as amiodarone and sotalol are associated with potential development of a specific and striking arrhythmia, torsades de pointes.
• Torsades a very fast ventricular arrhythmia, probably occurs when a set of associated features hypokalemia, bradycardia, and possibly delayed conduction alters membrane stability, promoting oscillations.
• Amiodarone like sotalol, is approved only for life-threatening arrhythmias.
• the drug blocks the sodium channels and to some extent the calcium channels, and it also has beta-blocking effects.
• side effects which are dose-related resulted in drug discontinuation in up to 20% of patients at one year.
• Cardiac toxicities include sinus bradycardia, atrioventricular block, congestive heart failure, and ventricular arrhythmias.
• Gap junctions are specialized regions of the cell membrane with clusters of hundreds to thousands of densely packed gap junction channels that directly connect the cytoplasmic compartment of two neighboring cells.
• the gap junction channels are composed of two hemichannels (connexons) provided by each of two neighboring cells.
• Each connexon consists of six proteins called connexins.
• the connexins are a large family of proteins all sharing the basic structure of four transmembrane domains, two extracellular loops, and a cytoplasmic loop. There is a high degree of conservation of the extracellular loops and transmembrane domains among species and connexin isoforms.
• the length of the C- terminus varies considerably giving rise to the classification of the connexins on the basis of the molecular weight.
• the distribution of the different types of connexins (Cx) varies throughout the heart.
• the Cx43 isoform is the predominant type in the ventricles whereas Cx40 is the must abundant isoform in the atrias and the conduction system.
• the gap junction channel can switch between an open and a closed state by a twisting motion. In the open state ions and small molecules smaller than about 1000 D can pass through the pore.
• the conduction of the electrical impulse takes place through the gap junctions and normally functioning gap junctions are therefore a prerequisite for normal conduction and thereby normal rhythm of the heart.
• mice homozygous for a targeted deletion of the Cx43 gene die shortly after birth from cardiac and pulmonary malformations, whereas heterozygous mice survive.
• the heterozygous genotype has a significantly slowed conduction compared to wild-type mice [2] .
• ventricular epicardial conduction of paced beats is slowed by 44% and QRS complexes of ECG recordings are significantly prolonged compared to those of wild-type mice.
• the reduced expression of Cx43 is directly linked to an increased incidence of ventricular arrhythmias during ischemia in mice heterozygous for the Cx43 gene deletion
• this peptide was named antiarrhytmic peptide (AAP) (Comparative Example 1 below (CE1)).
• AAP antiarrhytmic peptide
• CE1 antiarrhytmic peptide
• AAP10 H-Gly-Ala-Gly-4Hyp-Pro-Tyr-NH 2
• CE2 Comparative Example 2 below
• AAP10 had no effect on mean action potential duration, left ventricular end-diastolic pressure, coronary flow, QRS duration, or on the PQ interval. If hearts were subjected to regional ischemia by occlusion of the descending branch of the left coronary artery for 30 min, pretreatment with 10 nmol/l AAP10 led to a significant reduction in ischemia-induced alterations of activation patterns and reduced dispersion of activation-recovery intervals [18] . Additional studies showed that AAP10 did not affect the action potential in isolated papillary muscles from guinea pig hearts in concentrations up to 1 ⁇ mol/l [18] .
• the antiarrhythmic peptides are a group of peptides that exert their effect selectively on gap junctions and thus decrease cellular uncoupling and reduce dispersion of action potential duration and refractoriness without affecting the action potential duration or shape. Therefore, the antiarrhythmic peptides are expected to lack the proarrhythmic effects limiting the use of many currently available antiarrhythmic drugs. This makes the antiarrhythmic peptides extremely interesting as a potentially new and safer class of antiarrhythmic compounds.
• the native AAP as well as the synthetic AAP10 possess several undesired features, such as, low stability, high effective concentration etc. that has hitherto prevented their utilisation as drugs.
• cyclic depsipeptides having antiarrhythmic action but having an ester bond being labile towards endogenous esterases are disclosed in JP patent application No. 08281636 and in JP patent application No. 09308589.
• W096/21674 discloses AAP10 derivatives where a hydrogen at the phenyl ring of the tyrosine residue has been substituted with halogen. Said AAP10 derivatives have antiarrhythmic properties and a reduced proarrhythmic risk compared to lidocain and flecainid.
• the following AAP peptides and AAP-like compounds are described in the literature:
• Cyclo(CO-Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH) have shown activity or weak activity in test models, cf., e.g., Dhein and Tyduka (1995).
• GJIC gap junction intercellular communication
• the present peptides including antiarrhythmic peptide compounds that are characterised in having the following general formula I r X-A-B-Y ⁇ ⁇ --,- J where the dashed line indicates that formula I is optionally cyclic, and the bonds shown represent covalent bonds; and wherein A represents a chemical moiety having an amino group (radical) and a carboxy group (radical) that forms part of the peptide bond connecting A to X and B;
• B represents a chemical moiety having an amino group (radical) and a carboxy group (radical) that forms part of the peptide bond connecting B to A and Y;
• X represents a peptide sequence of from 1 to 3 amino acid residues which independently may be an L or D form when Y represents a C-terminal peptide sequence of from 2 to 5 amino acid residues which may independently be L- or D-forms;
• X represents an N-terminal modification of the group A-B when Y represents a C- terminal peptide sequence of from 2 to 5 amino acid residues which may independently be L- or D-forms; or
• X represents a peptide sequence of from 2 to 5 amino acid residues which may independently be L- or D-forms when Y represents a C-terminal peptide sequence of from 1 to 3 amino acid residues which independently may be an L or D form;
• formula I represents a linear peptide X is optionally chemically modified at its N- terminal, and L is an optional linking group comprising from 0 to 8 backbone atoms;
• Figure 1 is an illustration of different principles useful in the cyclisation of peptide sequences.
• Figure 2 shows the relative changes in intercellular conductance Gj as a function of time before and during stimulation with Compound 2 (10 "8 M), or vehicle in isolated guinea pig myocytes.
• the change in conductance is expressed as percent change relative to the conductance immediately prior to perfusion with Compound 2.
• Figure 3 shows phosphoinositol (PI) turnover as a function of noradrenalin concentration in cultures of cardiomyocytes isolated from neonatal Wistar rats, following 10 minutes of glucose and oxygen deprivation.
• Figure 4 shows the effect of Compound 2 on the attenuated noradrenaline-induced increase in phospho-inositol turnover during metabolic stress induced by ischemia and glucose starvation when added to the cardiomyocyte culture.
• Figure 5 shows measurements of the standard deviation of APD 90 as a measure of electrical dispersion (APD 90 dispersion) during four consecutive perfusion protocols. * indicates p ⁇ 0.05 versus the vehicle treated group.
• Figure 6 is an activation map of a dog heart where the purkinje layer is stimulated about two hours after coronary artery occlusion with epicardial (EPI) activation plane on the upper left and subepicardial (S-EPI), MIDWALL, subendocardial (S-ENDO), endocardial
• EPI epicardial
• S-EPI subepicardial
• MIDWALL subendocardial
• S-ENDO subendocardial
• FIG. 7 illustrates epicardial (E-) electrograms in the same dog from which examples are presented in Figures 6, 7, 8 and 9 recorded with surface lead ECG II and V5R during the second through fifth premature extra-stimuli (seen best on E-L) with ensuring 4 complexes of VT.
• the electrograms are recorded from the lateral, border zone (L) pacing site and east (E), north (N), centrally (C), subepicardially (SE), below E-C, as well as south (S), and northwest (NW), and southwest (SW) of E-C.
• Figure 8 illustrates epicardial activation of the first complex of the ventricular tachycardia which starts at -44 msec prior to the onset of the surface QRS and which corresponds to the electrogram recorded at E-C in Figure 7.
• Activation proceeds in a double loop reentry activating first at -17 msec and then proceeding to 57 msec on the northwest loop.
• Figure 9 shows the same leads from the same dog(s?) as presented in Figure 7.
• This figure illustrates the epicardial (E-) electrograms recorded during stimulation of the same site as used in Figure 7, but after i.v. after administration of Compound 2. After 30 minutes a second dose of Compound 2 was given, and after an additional 30 min a third dose was given. No VT was inducible after administration of either of these doses for up to an hour and a half after antiarrhythmic peptide was administered.
• Figure 10 shows the short-term effect of lxlO "8 M of Compound 2 on intercellular calcium wave propagation in human osteoblasts. Number of cells in wave before (1) and 10 minutes after adding Compound 2 (2) to the bathing solution is plotted. Figure 11 shows the number of cells in the calcium wave plotted before (1) and 10 minutes after addition of lxlO "8 M of Compound 2 (2) to ROS 17/2.8 cells, cultured under hypoxic conditions (5% 0 2 ).
• Figure 12 illustrates dye transfer in ROS 17/2.8 cells, cultured under hypoxic conditions (3-6% 0 2 ). Number of coupled cells is plotted before (1) and 10 minutes after adding lxlO "8 M of Compound 2 to the bathing solution (2).
• Figure 13 illustrates the short-term effect of lxlO "8 M of Compound 2 on intercellular calcium wave propagation in human osteoblasts under hypoglycemic conditions. The figure shows the number of cells in the wave during hypoglycemia (1) and 10 minutes after adding Compound 2 to the hypoglycemic bathing solution (2).
• Figure 14 shows alkaline phosphatase (ALP) activity in cultures of human osteoblastic cells. The ALP activity is a measure of osteoblastic activity.
• ALP alkaline phosphatase
• ALP activity was measured over four days stimulation with 10 "13 - 10 "6 M of Compound 2 in each culture, and compared to untreated controls. The ratio between the ALP activity in the treated and untreated cultures are plotted for each concentration of the compound. Compound 2 stimulated ALP activity and thus osteoblastic activity at all concentrations in the concentration range 10 "13 - 10 "7 M.
• Figure 15 shows the effect of Compound 2 on Lucifer Yellow (LY) dye transfer in human osteoblast cells treated with 13 ⁇ M DDT, the compound l,l-bis(p-chlorophenyl)-2,2,2- trichlorethane. 10 minutes incubation with 10 "8 M of Compound 2 produced an increase in the number of dye-coupled coupled cells in all experiments (1 indicated before and 2 indicated after addition of Compound 2 to the bath).
• LY Lucifer Yellow
• the covalent bonds are selected from peptide bonds, disulphide bonds, ester bonds, reduced amide bonds, alkoxy bonds, oxycarbonyl bonds, and acyloxyalkoxy bonds.
• Examples of A and B include the formula II (II)
• n is an integer having the value 3, 4, or 5
• R represents an optional substituent, preferably selected from the group consisting of halogen, phenyl, hydroxy, NH2, and C(l-6)alkyl.
• a and B each represents an amino acid or an amino acid derivative having functional amino and carboxylic acid groups. Further examples of A and B are represented by the formula Ila
• n is an integer having the value 0, 1, 2, and 3
• p is an integer having the value 0,
• Z represents O or S
• R represents an optional substituent, preferably selected from the group consisting of halogen, phenyl, hydroxy, NH2, and C(l-6)alkyl.
• a and B include but are not limited to N- and C(O)- radicals of the following compounds: D/L-azetidin-3-carboxylic acid,
• the chemical moiety of A and B each represents an amino acid residue having a saturated carbocyclic structure of 4, 5 or 6 members comprising one or more heteroatoms, such as N and S.
• Said amino acids include L and D forms, natural and unnatural amino acids and derivatives thereof, such as a Prolin residue having one or more substituents in the 3, 4 or 5 position, said substituents being preferably selected from hydroxy, amino or phenyl; and N-substituted amino acids, such as Sarcosin, N- cyclohexylglycine, and N-phenylglycine.
• sequence A-B represents a dipeptide selected from the group consisting of Sar-Sar, Sar-Hyp, Hyp-Sar, Pro-Sar, Sar-Pro, Pro-Hyp, Pro-Pro, Hyp-Pro, and Hyp-Hyp, where Pro and Hyp independently may be an L or D form, where the ring structure of Pro and Hyp is optionally substituted with halogen, nitro, methyl, amino, or phenyl, and Hyp represents 3-hydroxyproline or 4-hydroxyproline, or one or both of the amino acid residues of A-B is a Sar, or N-cyclohexylglycine residue;
• formula I represents a linear peptide wherein said chemical modification of the N-terminal of X is
• an acylation with an optionally substituted C(l-22)alkyl carboxylic acid such as acetic acid, propionic acid, butyric acid and other fatty acids, or an optionally substituted C(2- 22)alkenyl carboxylic acid, or an aryl carboxylic acid, such as benzoic acid, where the substitutent is selected from hydroxy, halogen, C(l-6)alkyl, nitro or cyano and may be situated on the carbon chain or the aromatic moiety; or
• X is selected from the group consisting of L-Tyr and D-Tyr optionally acylated with a C(l-4)carboxylic acid, preferably acetic acid, when Y represents a C- terminal peptide sequence of from 2 to 5 amino acid residues as defined above.
• X represents an N-terminal modification of the group A-B, said modifications being preferably selected from phenylpropionic acid and derivatives thereof, such as 4HPP and 2HPP; phenylacetic acid and derivatives thereof, such as 4HPA, 3HPA and 2HPA; phenoxyacetic acid and derivatives thereof, such as 4HPPA, 2HPPA and 4HMPA; benzoylglycine and derivatives thereof, such as 4HBG, 3HBG and 2HBG; and phenylglycine and derivatives thereof bound via an amide bond to A.
• phenylpropionic acid and derivatives thereof such as 4HPP and 2HPP
• phenylacetic acid and derivatives thereof such as 4HPA, 3HPA and 2HPA
• phenoxyacetic acid and derivatives thereof such as 4HPPA, 2HPPA and 4HMPA
• benzoylglycine and derivatives thereof such as 4HBG, 3HBG and 2HBG
• A-B is more preferably selected from the group consisting of Pro-Hyp, Pro-Pro, Hyp-Pro, and Hyp-Hyp where Pro and Hyp independently may be an L or D form and Hyp preferably represents 4Hyp.
• Y represents a peptide of from 3 to 5 amino acid residues, or preferably 3 or 4 amino acid residues, being independently L- or D-forms, and preferably having Sar or Gly at its C-terminal, and more preferably Y represents a peptide sequence selected from the group consisting of
• formula I represents a cyclic peptide wherein A-B is selected from the group consisting of
• A-B represents unsubstituted L-Pro-L-4Hyp, L-4Hyp-L- Pro, D-Pro-D-4Hyp, or D-4Hyp-D-Pro.
• X represents a single amino acid residue, preferably L-Tyr or D-Tyr optionally further substituted with halogen, phenyl, hydroxy, NH 2 , and C(l-6)alkyl optionally substituted with halogen, at its aromatic ring when Y represents a peptide of 3 or 4 amino acid residues being independently L- or D-forms, preferably having Asp or Glu at its C- terminal, and more preferably when Y represents a peptide sequence selected from the group consisting of
• Or X represents a peptide sequence preferably selected from the group consisting of Gly-L-Ala-L-Asp,
• Gly-D-Ala-Gly-D-Glu when Y represents a single amino acid residue, preferably L-Tyr or D-Tyr optionally further substituted with halogen, such as Cl, at its aromatic ring.
• Formula I may represent a cyclic peptide sequence comprising all L-forms, all D-forms, or a sequence of mixed L- and D-forms of the amino acid residues.
• formula I represents a cyclic compound where the groups X and Y are connected via an amino carbonyl bond, an alkoxy bond, an ester bond, a reduced amide bond, or a disulphide bond.
• R' and R" each represents hydrogen or lower alkyl and/or lower aryl, preferably methyl and phenyl are listed below
• R' and R" each represents hydrogen or lower alkyl and/or lower aryl, preferably methyl and phenyl, preferably R' ⁇ R", are listed below:
• L may be derived from a hydroxy-carboxylic acid, such as a hydroxy C(3-6)alkyl carbocylic acid.
• L is derived from an ⁇ -hydroxy-carboxylic acid preferably of the general formula HO-C(Rl)(R2)-COOH wherein RI and R2 independently is H, C(l-6)-alkyl, C(2-6)-alkenyl, aryl, aryl-C(l-4)-alkyl, heteroaryl or heteroaryl-C(l-4)-alkyl; or RI and R2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring; where an alkyl or alkenyl group may be substituted with from one to three substituents selected from amino, cyano, halogen, isocyano, isothiocyano
• RI and R2 represent different groups.
• the group A-B is selected from the group consisting of Sar-Hyp, Hyp-Sar, Pro-Hyp, Pro-Pro, Hyp-Pro, and Hyp-Hyp where Pro and
• Hyp independently may be an L or D form and Hyp preferably represents 4- hydroxyproline. More preferably, A-B represents unsubstituted L-Pro-L-4Hyp, L-4Hyp-L-

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• 2001
  • 2001-02-22 DE DE60107803T patent/DE60107803T2/de not_active Expired - Lifetime
  • 2001-02-22 AU AU35362/01A patent/AU781674B2/en not_active Ceased
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  • 2001-02-22 JP JP2001562556A patent/JP4327398B2/ja not_active Expired - Fee Related
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  • 2001-02-22 ES ES01907393T patent/ES2228807T3/es not_active Expired - Lifetime
  • 2001-02-22 PT PT01907393T patent/PT1226160E/pt unknown
• 2003
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