Compositions and methods for effecting NAD+ levels using a nicotinamide phosphoribosyl tranferase inhibitor

1. A method for treating a patient diagnosed with or suspected to have a cancer deficient in nicotinic acid pathway comprising administering to the patient:

(a) an effective amount of a nicotinamide phosphoribosyl transferase inhibitor; and

(b) an effective amount of nicotinic acid.

2. The method of claim 1 , wherein the cancer is sarcoma, glioblastoma, or neuroblastoma.

3. The method of claim 1 , wherein the nicotinamide phosphoribosyl transferase inhibitor is an effective amount of the compound of the formula Ia

the formula Ib

the formula II

or a pharmaceutically acceptable salt thereof,

wherein X 1 and X 2 are independently a bond, a straight, branched and/or cyclic hydrocarbon diradical which is unsubstituted or substituted with one or more hydroxy, halogen, nitro, amino, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino; a heteroarylene or non-aromatic heterocyclic hydrocarbon diradical, each of which is unsubstituted or substituted with one or more straight, branched and/or cyclic non-aromatic hydrocarbon radical, hydroxyl, halogen, amino, nitro, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino;

each Y 1 and Y 2 is independently a bond, an ether diradical (R′—O—R″), an amine diradical (R′—N—R″), O, S, S(O), S(O) 2 , C(O), NH—CO, CO—NH, SO 2 —N(R′), methylene or N(R)—SO 2 wherein R′ and R″ are independently a straight or branched hydrocarbon diradical containing 1-4 carbon atoms;

Y 3 is O, O—C(O), C(O)—O, or N(R 8 ); R 8 is hydrogen or C 1-4 alkyl;

R 1 is hydrogen or straight, branched and/or cyclic alkyl, all of which other than hydrogen are unsubstituted or substituted with phenyl; or an aromatic hydrocarbon radical;

R 2 is aryl, heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, tetrahydropyranyloxy, di-(C 1-4 alkoxy)phosphinoyloxy and C 1-4 alkoxycarbonylamino, all of which can be unsubstituted or substituted with one or more of halogen, trifluoromethyl, hydroxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, amino, aminocarbonyl, sulfamoyl, C 1-4 alkyl or C 1-4 hydroxyalkyl, wherein the C 1-4 alkyl and C 1-4 hydroxyalkyl are unsubstituted or substituted with one or more of halogen, hydroxyl, cyano or nitro;

R 3 is hydrogen, a straight, branched and/or cyclic hydrocarbon radical, all of which other than hydrogen can be substituted with one or more amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which can be substituted with one or more straight, branched and/or cyclic hydrocarbon radical, amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl;

wherein s is an integer from 1 to 200; R 6 is hydrogen or a substituted or unsubstituted non-aromatic hydrocarbon radical; each R 7 is independently hydrogen or methyl;

each R 4 and R 5 is independently represent hydrogen; a straight, branched and/or cyclic hydrocarbon radical, all of which other than hydrogen can be substituted with one or more of halogen, hydroxyl, halogen, amino, nitro or cyano;

A represents hydrogen, an substituted or unsubstituted straight, branched and/or cyclic hydrocarbon radical, hydroxy, halogen, nitro, cyano, heteroaryl, heteroaralkyl or thiol;

Z − is a pharmaceutically acceptable anion;

each m and r is independently an integer from 0 to 4; and n is 0 or 1.

4. The method of claim 3 , wherein the compound of formula Ia, Ib, or II is:

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-Methoxyethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-Methoxyethoxy)-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

N-[1-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxycarbonyloxymethyl)-1,4-dihydropyridin-4-ylidene]-N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-guanidine;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[1-(2-(2-Methoxyethoxy)-ethoxy-carbonyloxy)-ethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-acetoxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-Pivaloyloxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-Acetoxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-(L)-Valyloxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-Glycyloxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[Monobenzyl succinyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy)-ethoxy carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-ethoxy-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(9-(diethoxyphosphinoyloxy)-nonyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-carbonyloxymethyl]-4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridinium iodide;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-carbonyloxymethyl]-4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridinium chloride;

1-[3-(N-tert-butoxycarbonylamino)-propyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[3-Amino-propyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[3-(N-tert-butoxycarbonylamino)-propyl-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[3-Aminopropyl-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[5-(N-tert-butoxycarbonylamino)-pentanoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[5-Amino-pentanoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[3-(tert-butoxycarbonyl)-propionyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[3-carboxy-propionyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[N-(tert-butoxycarbonylmethyl)-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[N-(carboxymethyl)-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[1-(tert-butoxycarbonyl)-4-piperidyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[4-Piperidyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chloro-phenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[tert-butoxycarbonylmethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[Carboxymethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

N-[1-(α-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxycarbonyloxy)benzyl)-1,4-dihydropyridin-4-ylidene]-N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-guanidine;

4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridine;

4-[N′-cyano-N″-(9-(diethoxyphosphinoyloxy)-nonyl)-N-guanidino]-pyridine;

4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridine;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 4 , wherein the compound is 1-[2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride, 4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridine, or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the nicotinamide phosphoribosyl transferase inhibitor is (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)acrylamide.

7. The method of any one of claims 1 - 6 , wherein the effective amount of nicotinic acid is administered intravenously at a dose of about 90 mg/m 2 for at least four hours.

8. The method of any one of claims 1 - 6 , wherein the effective amount of nicotinic acid is administered orally.

9. The method of any one of claims 1 - 6 , wherein the nicotinamide phosphoribosyl transferase inhibitor is administered prior to or subsequent to nicotinic acid.

10. The method of any one of claims 1 - 6 , wherein the nicotinamide phosphoribosyl transferase inhibitor is administered concurrently with the administration of nicotinic acid.

11. A method for treating a patient diagnosed with or suspected to have a cancer deficient in nicotinic acid pathway comprising administering to the patient:

(a) an effective amount of a nicotinamide phosphoribosyl transferase inhibitor;

(b) an effective amount of nicotinic acid; and

(c) DNA damaging therapy.

12. The method of claim 11 , wherein the cancer is sarcoma, glioblastoma, or neuroblastoma.

13. The method of claim 11 , wherein the nicotinamide phosphoribosyl transferase inhibitor is the compound of the formula Ia

the formula Ib

the formula II

or a pharmaceutically acceptable salt thereof,

wherein X 1 and X 2 are independently a bond, a straight, branched and/or cyclic hydrocarbon diradical which is unsubstituted or substituted with one or more hydroxy, halogen, nitro, amino, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino; a heteroarylene or non-aromatic heterocyclic hydrocarbon diradical, each of which is unsubstituted or substituted with one or more straight, branched and/or cyclic non-aromatic hydrocarbon radical, hydroxyl, halogen, amino, nitro, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino;

each Y 1 and Y 2 is independently a bond, an ether diradical (R′—O—R″), an amine diradical (R′—N—R″), O, S, S(O), S(O) 2 , C(O), NH—CO, CO—NH, SO 2 —N(R′), methylene or N(R)—SO 2 wherein R′ and R″ are independently a straight or branched hydrocarbon diradical containing 1-4 carbon atoms;

Y 3 is O, O—C(O), C(O)—O, or N(R 8 ); R 8 is hydrogen or C 1-4 alkyl;

R 1 is hydrogen or straight, branched and/or cyclic alkyl, all of which other than hydrogen are unsubstituted or substituted with phenyl; or an aromatic hydrocarbon radical;

R 2 is aryl, heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, tetrahydropyranyloxy, di-(C 1-4 alkoxy)phosphinoyloxy and C 1-4 alkoxycarbonylamino, all of which can be unsubstituted or substituted with one or more of halogen, trifluoromethyl, hydroxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, amino, aminocarbonyl, sulfamoyl, C 1-4 alkyl or C 1-4 hydroxyalkyl, wherein the C 1-4 alkyl and C 1-4 hydroxyalkyl are unsubstituted or substituted with one or more of halogen, hydroxyl, cyano or nitro;

R 3 is hydrogen, a straight, branched and/or cyclic hydrocarbon radical, all of which other than hydrogen can be substituted with one or more amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which can be substituted with one or more straight, branched and/or cyclic hydrocarbon radical, amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl;

wherein s is an integer from 1 to 200; R 6 is hydrogen or a substituted or unsubstituted non-aromatic hydrocarbon radical; each R 7 is independently hydrogen or methyl;

each R 4 and R 5 is independently represent hydrogen; a straight, branched and/or cyclic hydrocarbon radical, all of which other than hydrogen can be substituted with one or more of halogen, hydroxyl, halogen, amino, nitro or cyano;

A represents hydrogen, an substituted or unsubstituted straight, branched and/or cyclic hydrocarbon radical, hydroxy, halogen, nitro, cyano, heteroaryl, heteroaralkyl or thiol;

Z − is a pharmaceutically acceptable anion;

each m and r is independently an integer from 0 to 4; and n is 0 or 1.

14. The method of claim 13 , wherein the compound of formula Ia, Ib, or II is:

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-Methoxyethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-Methoxyethoxy)-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

N-[1-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxycarbonyloxymethyl)-1,4-dihydropyridin-4-ylidene]-N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-guanidine;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[1-(2-(2-Methoxyethoxy)-ethoxy-carbonyloxy)-ethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-acetoxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-Pivaloyloxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-Acetoxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-(L)-Valyloxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-Glycyloxymethyl-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[Monobenzyl succinyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy)-ethoxy carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-ethoxy-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(9-(diethoxyphosphinoyloxy)-nonyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-carbonyloxymethyl]-4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridinium iodide;

1-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-carbonyloxymethyl]-4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridinium chloride;

1-[2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridinium chloride;

1-[3-(N-tert-butoxycarbonylamino)-propyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[3-Amino-propyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[3-(N-tert-butoxycarbonylamino)-propyl-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[3-Aminopropyl-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[5-(N-tert-butoxycarbonylamino)-pentanoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[5-Amino-pentanoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[3-(tert-butoxycarbonyl)-propionyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[3-carboxy-propionyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[N-(tert-butoxycarbonylmethyl)-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[N-(carboxymethyl)-carbamoyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[1-(tert-butoxycarbonyl)-4-piperidyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[4-Piperidyloxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chloro-phenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

1-[tert-butoxycarbonylmethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium iodide;

1-[Carboxymethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride;

N-[1-(α-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxycarbonyloxy)benzyl)-1,4-dihydropyridin-4-ylidene]-N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-guanidine;

4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridine;

4-[N′-cyano-N″-(9-(diethoxyphosphinoyloxy)-nonyl)-N-guanidino]-pyridine;

4-[N′-cyano-N″-(12-(tert-butyloxycarbonylamino)-dodecyl)-N-guanidino]-pyridine;

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the compound is 1-[2-(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-ethoxy-carbonyloxymethyl]-4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride, 4-[N′-cyano-N″-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridine, or a pharmaceutically acceptable salt thereof.

16. The method of claim 11 , wherein the nicotinamide phosphoribosyl transferase inhibitor is (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)acrylamide.

17. The method of any one of claims 11 - 16 , wherein the effective amount of nicotinic acid is administered intravenously at a dose of about 90 mg/m 2 for at least four hours.

18. The method of any one of claims 11 - 16 , wherein the effective amount of nicotinic acid is administered orally.

19. The method of any one of claims 11 - 16 , wherein nicotinic acid is administered prior or subsequent to the administration of the nicotinamide phosphoribosyl transferase inhibitor.

20. The method of any one of claims 11 - 16 , wherein nicotinic acid is administered concurrently with the administration of the nicotinamide phosphoribosyl transferase inhibitor.

21. The method of any one of claims 11 - 16 , wherein the DNA damaging therapy is administered subsequent to the administration of the nicotinamide phosphoribosyl transferase inhibitor and nicotinic acid.

22. The method of any one of claims 11 - 16 , wherein the DNA damaging therapy is administered concurrently with the administration of the nicotinamide phosphoribosyl transferase inhibitor and nicotinic acid.

23. The method of claim 11 - 16 , wherein the DNA damaging therapy comprises administering the patient an effective amount of a DNA damaging chemotherapeutic agent.

24. The method of claim 23 , wherein the DNA damaging chemotherapeutic agent is Cladribine, Pentostatin, Methotrexate, Trimetrexate glucuronate, Pemetrexed, Treosulfan, Busulfan, Dacarbazine, Temozolomide, Mitomycin C, Chlorambucil, Ifosfamide, Melphalan, Thiotepa, Mechlorethamine, Carmustine, Bendamustin, Fotemustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Lobaplatin, Oxaliplatin Bleomycin, Hydroxyurea, Actinomycin D, Azacitidine, Decitabine, Nelarabine, Cytarabine, Fludarabine, Clofarabine, Vorinostat, Gemcitabine, 5-Fluorouracil, Capecitabine, Floxuridine, Raltitrexed, Pemetrexed, Irinotecan, Topotecan, Amrubicin, Daunorubicin, Doxorubicin, Epirubicin, Etoposide, Idarubicin, Mitoxantrone, Teniposide, Valrubicin, Allopurinol, or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 11 - 16 , wherein the DNA damaging therapy comprises radiation therapy.