Method of predicting a predisposition to qt prolongation

Abstract

The present invention describes an association between genetic polymorphisms in the ABCC2 gene and a predisposition to prolongation of the QT interval, and provides related methods for the prediction of such a predisposition, the administration of QT interval-prolonging compounds to individuals having such a predisposition, and determining whether a compound is capable of inducing QT prolongation.

1 . A method of administering to an individual a compound capable of prolonging the individual's QT interval, the method comprising:
 determining at least a portion of an individual's ABCC2 gene sequence; and   in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a quantity of the compound less than would be administered to an individual having a ABCC2 gene sequence not associated with an increased risk of QT prolongation.   
     
     
         2 . The method of  claim 1 , wherein determining includes determining the individual's genotype at the rs7067971 locus, and wherein the genotype associated with an increased risk of QT prolongation is GG. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , further comprising:
 determining the individual's CYP2D6 genotype.   
     
     
         5 . The method of  claim 1 , wherein the compound is selected from a group consisting of:
 amiodarone, arsenic trioxide, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, iloperidone, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine;   alfuzosin, amantadine, azithromycin, chloral hydrate, clozapine, dolasetron, felbamate, flecainide, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisetron, indapamide, isradipine, levofloxacin, lithium, moexipril, moxifloxacin, nicardipine, octreotide, ofloxacin, ondansetron, quetiapine, ranolazine, risperidone, roxithromycin, tacrolimus, tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, voriconazole, ziprasidone;   albuterol, amitriptyline, amoxapine, amphetamine, dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram, clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine, dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole, fluoxetine, galantamine, imipramine, isoproterenol, itraconazole, ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine, midodrine, norepinephrine, nortriptyline, paroxetine, phentermine, phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine, ritodrine, salmeterol, sertraline, sibutramine, solifenacin, terbutaline, tolterodine, trimethoprim-sulfa, trimipramine, and metabolites, pharmaceutically-acceptable salts, and combinations thereof.   
     
     
         6 . The method of  claim 5 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid, pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl, 
       
       
         
           
           
               
               
           
         
       
       alkyl is lower alkyl, branched or straight and saturated or unsaturated;
   acyl is lower alkyl or lower alkyloxy bonded through a carbonyl;   aryl is phenyl or phenyl substituted with at least one group, R 5 , wherein each R 5  is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;   heteroaryl is a five- or six-membered aryl ring having at least one heteroatom, Q 3 , wherein each Q 3  is, independently, —O—, —S—, —N(H)—, or —C(H)═N—   W is CH 2  or CHR 8  or N—R 9 ;   
 R 1  is —H, lower alkyl, —OH, halo, lower alkoxy, trifluormethyl, nitro, or amino; 
 R 2  is C 2 -C 5  alkylene, alkenylene (cis or trans), or alkynylene, optionally substituted by at least one C 1 -C 6  linear alkyl group, phenyl group or 
 
       
         
           
           
               
               
           
         
       
       where Z 1  is lower alkyl, —OH, lower alkoxy, —CF 3 , —NO 2 , —NH 2 , or halogen;
 R 3  is lower alkyl or hydrogen; 
 R 7  is hydrogen, lower alkyl, or acyl; 
 R 8  is lower alkyl; 
 R 9  is hydroxy, lower alkoxy, or —NHR 10 ; 
 R 10  is hydrogen, lower alkyl, C 1 -C 3  acyl, aryl, 
 
       
         
           
           
               
               
           
         
         X 1 , X 2 , and X 3  are, independently, —O—, —S—, ═N—, or —N(R 3 )—, or X 1  and X 2  are not covalently bound to each other and are, independently, —OH, ═O, —R 3 , or ═NR 3 ; 
         lower is 1-4 carbon atoms; 
         m is 1, 2, or 3; and 
         n is 1 or 2. 
       
     
     
         7 . The method of  claim 6 , wherein:
 R is —C(O)CH 2 OH, —CH(OH)C(O)CH 2 OH, —C(O)OH, CH(OH)CH 3 , or C(O)CH 3 ;   R 1  is halo;   X 1  and X 2  are different and are ═O, —OH, ═N—, or —O—;   R 2  is C 2 -C 4  alkylene or alkenylene;   R 3  is hydrogen, methyl, or ethyl;   X 3  is —O—;   R is   
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7 , wherein the compound of Formula 1 is 1-[4-3-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 7 , wherein the compound of Formula 1 is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 1C: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A method of determining whether an individual is predisposed to prolongation of the QT interval, the method comprising:
 determining at least a portion of an individual's ABCC2 gene sequence.   
     
     
         11 . The method of  claim 10 , further comprising:
 in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a compound not known or suspected to cause QT prolongation.   
     
     
         12 . The method of  claim 10 , wherein determining includes determining the individual's genotype at the rs7067971 locus, and wherein the genotype associated with an increased risk of QT prolongation is GG. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 10 , further comprising:
 determining the individual's CYP2D6 genotype.   
     
     
         15 . A method of administering a compound capable of prolonging a QT interval to an individual suffering from long QT syndrome (LQTS), the method comprising:
 determining at least a portion of an individual's ABCC2 gene sequence; and   administering to the individual a quantity of the compound based on the individual's ABCC2 gene sequence.   
     
     
         16 . The method of  claim 15 , wherein determining includes determining the individual's genotype at the rs7067971 locus, and wherein the genotype associated with an increased risk of QT prolongation is GG. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 15 , further comprising:
 determining the individual's CYP2D6 genotype.   
     
     
         19 . The method of  claim 15 , wherein the compound is selected from a group consisting of:
 amiodarone, arsenic trioxide, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, iloperidone, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine;   alfuzosin, amantadine, azithromycin, chloral hydrate, clozapine, dolasetron, felbamate, flecainide, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisetron, indapamide, isradipine, levofloxacin, lithium, moexipril, moxifloxacin, nicardipine, octreotide, ofloxacin, ondansetron, quetiapine, ranolazine, risperidone, roxithromycin, tacrolimus, tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, voriconazole, ziprasidone;   albuterol, amitriptyline, amoxapine, amphetamine, dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram, clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine, dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole, fluoxetine, galantamine, imipramine, isoproterenol, itraconazole, ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine, midodrine, norepinephrine, nortriptyline, paroxetine, phentermine, phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine, ritodrine, salmeterol, sertraline, sibutramine, solifenacin, terbutaline, tolterodine, trimethoprim-sulfa, trimipramine, and metabolites, pharmaceutically-acceptable salts, and combinations thereof.   
     
     
         20 . The method of  claim 19 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid, pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl, 
 
       
         
           
           
               
               
           
         
       
       alkyl is lower alkyl, branched or straight and saturated or unsaturated;
   acyl is lower alkyl or lower alkyloxy bonded through a carbonyl;   aryl is phenyl or phenyl substituted with at least one group, R 5 , wherein each R 5  is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;   heteroaryl is is a five- or six-membered aryl ring having at least one heteroatom, Q 3 , wherein each Q 3  is, independently, —O—, —S—, —N(H)—, or —C(H)═N—   W is CH 2  or CHR 8  or N—R 9 ;   
 R 1  is —H, lower alkyl, —OH, halo, lower alkoxy, trifluormethyl, nitro, or amino; 
 R 2  is C 2 -C 5  alkylene, alkenylene (cis or trans), or alkynylene, optionally substituted by at least one C 1 -C 6  linear alkyl group, phenyl group or 
 
       
         
           
           
               
               
           
         
       
       where Zi is lower alkyl, —OH, lower alkoxy, —CF 3 , —NO 2 , —NH 2 , or halogen;
 R 3  is lower alkyl or hydrogen; 
 R 7  is hydrogen, lower alkyl, or acyl; 
 R 8  is lower alkyl; 
 R 9  is hydroxy, lower alkoxy, or —NHR 10 ; 
 R 10  is hydrogen, lower alkyl, C 1 -C 3  acyl, aryl, 
 
       
         
           
           
               
               
           
         
         X 1 , X 2 , and X 3  are, independently, —O—, —S—, ═N—, or —N(R 3 )—, or X 1  and X 2  are not covalently bound to each other and are, independently, —OH, ═O, —R 3 , or ═NR 3 ; 
         lower is 1-4 carbon atoms; 
         m is 1, 2, or 3; and 
         n is 1 or 2. 
       
     
     
         21 . The method of  claim 20 , wherein:
 R is —C(O)CH 2 OH, —CH(OH)C(O)CH 2 OH, —C(O)OH, CH(OH)CH 3 , or C(O)CH 3 ;   R 1  is halo;   X 1  and X 2  are different and are ═O, —OH, ═N—, or —O—;   R 2  is C 2 -C 4  alkylene or alkenylene;   R 3  is hydrogen, methyl, or ethyl;   X 3  is —O—;   R is   
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 21 , wherein the compound of Formula 1 is 1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 21 , wherein the compound of Formula 1 is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 1C: 
       
         
           
           
               
               
           
         
       
     
     
         24 - 33 . (canceled)