METHOD OF PREDICTING A PREDISPOSITION TO 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 BAI3 gene sequence; and

in the case that a portion of the individual's BAI3 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 BAI3 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 rs1083338 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 BAI3 gene sequence.

11 . The method of claim 10 , further comprising:

in the case that a portion of the individual's BAI3 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 rs1083338 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 BAI3 gene sequence; and

administering to the individual a quantity of the compound based on the individual's BAI3 gene sequence.

16 . The method of claim 15 , wherein determining includes determining the individual's genotype at the rs1083338 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 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.

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)