Method of treatment based on polymorphisms of the kcnq1 gene

Abstract

The invention provides methods for the administration of compounds capable of prolonging a QTc interval and methods for predicting whether an individual is predisposed to such QTc prolongation.

What is claimed is: 
     
         1 . A method of treating a patient with a compound capable of prolonging the QT interval, the method comprising:
 determining at least a portion of the patient's KCNQ1 gene sequence; and   administering to the patient a quantity of the compound based on the patient's KCNQ1 gene sequence.   
     
     
         2 . The method of  claim 1 , wherein the quantity of the compound administered is less if the patient's KCNQ1 genotype at position 79764 of reference sequence AJ006345.1 is GG than if the patient's genotype is not GG. 
     
     
         3 . The method of  claim 1 , wherein the quantity of the compound administered is less if the patient's KCNQ1 genotype at position 286414 of reference sequence AJ006345.1 is AA than if the patient's genotype is not AA. 
     
     
         4 . The method of  claim 1 , wherein the quantity of the compound administered is less if the patient's KCNQ1 genotype at position 78927 of reference sequence AJ006345.1 is CC than if the patient's genotype is not CC. 
     
     
         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—; and   R is substituted as shown in Formula 1A   
       
         
           
           
               
               
           
         
       
     
     
         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 . The method of  claim 1 , further comprising:
 determining at least a portion of the patient's CYP2D6 gene sequence.   
     
     
         11 . The method of  claim 10 , wherein the quantity of the compound administered is less if the patient's CYP2D6G1846A genotype is AA or GA than if the patient's genotype is GG. 
     
     
         12 . The method of  claim 10 , wherein the quantity of the compound administered is less if the patient's CYP2D6C100T genotype is TT or CT than if the patient's genotype is CC. 
     
     
         13 . The method of  claim 1 , wherein the patient is suffering from at least one condition selected from a group consisting of: schizophrenia, schizoaffective disorder, depression, bipolar mania/depression, cardiac arrythmia, Tourette's Syndrome, a psychotic disorder, a delusional disorder, and schizophreniform disorder. 
     
     
         14 . The method of  claim 13 , wherein the patient is suffering from at least one condition selected from a group consisting of: paranoid schizophrenia, catatonic schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, and residual schizophrenia. 
     
     
         15 . The method of  claim 13 , wherein the patient is suffering from at least one condition selected from a group consisting of: brief psychotic disorder, a psychotic disorder not otherwise specified, a psychotic disorder due to a general medical condition, and a substance-induced psychotic disorder. 
     
     
         16 . A method of determining whether an individual is predisposed to prolongation of the QTc interval, the method comprising:
 determining at least a portion of an individual's KCNQ1 gene sequence.   
     
     
         17 . The method of  claim 16 , wherein determining includes determining the individual's genotype at at least one single nucleotide polymorphism (SNP) locus selected from a group consisting of: 79764 of reference sequence AJ006345.1, position 286414 of reference sequence AJ006345.1, and position 78927 of reference sequence AJ006345.1. 
     
     
         18 . The method of  claim 18 , further comprising:
 concluding that the individual is predisposed to prolongation of the QTc interval if the individual's KCNQ1 genotype includes any of the following:   GG at position 79764 of reference sequence AJ006345.1;   AA at position 286414 of reference sequence AJ006345.1; or   CC at position 78927 of reference sequence AJ006345.1.   
     
     
         19 . The method of  claim 16 , further comprising:
 determining at least a portion of the individual's CYP2D6 gene sequence.   
     
     
         20 . The method of  claim 19 , wherein determining includes determining whether the individual's CYP2D6 gene sequence includes the CYP2D6G1846A polymorphism. 
     
     
         21 . The method of  claim 19 , wherein determining includes determining whether the individual's CYP2D6 gene sequence includes the CYP2D6C100T polymorphism. 
     
     
         22 . A method of treating a patient with a compound capable of prolonging the QT interval, the method comprising:
 characterizing an expression product of the patient's KCNQ1 gene; and   administering to the patient a quantity of the compound based on the characterized expression product.   
     
     
         23 . The method of  claim 22 , wherein the quantity of the compound is reduced if the characterized expression product corresponds to any of the following:
 a GG KCNQ1 genotype at position 79764 of reference sequence AJ006345.1;   an AA KCNQ1 genotype at position 286414 of reference sequence AJ006345.1; or   a CC KCNQ1 genotype at position 78927 of reference sequence AJ006345.1.   
     
     
         24 . The method of  claim 22 , further comprising:
 characterizing an expression product of the patient's CYP2D6 gene.   
     
     
         25 . The method of  claim 24 , further comprising:
 determining whether the characterized expression product corresponds to a CYP2D6 polymorphism selected from a group consisting of: CYP2D6G1846A and CYP2D6C100T.   
     
     
         26 . The method of  claim 22 , 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.   
     
     
         27 . A method of determining whether an individual is predisposed to prolongation of the QTc interval, the method comprising:
 characterizing an expression product of an individual's KCNQ1 gene.   
     
     
         28 . The method of  claim 27 , further comprising:
 determining whether the characterized expression product corresponds to any of the following:   a GG KCNQ1 genotype at position 79764 of reference sequence AJ006345.1;   an AA KCNQ1 genotype at position 286414 of reference sequence AJ006345.1; or   a CC KCNQ1 genotype at position 78927 of reference sequence AJ006345.1.   
     
     
         29 . The method of  claim 27 , further comprising:
 characterizing an expression product of the individual's CYP2D6 gene.   
     
     
         30 . The method of  claim 29 , further comprising:
 determining whether the characterized expression product corresponds to a CYP2D6 polymorphism selected from a group consisting of: CYP2D6G1846A and CYP2D6C100T.