Tissue non-specific alkaline phosphatase inhibitors and uses thereof for treating vascular calcification

1. A method of treating vascular calcification in a subject, comprising administering one or more compounds having one of the following formula:

wherein A 2 represents —N—;

wherein A 1 , A 3 , A 4 , A 5 , A 6 , and A 7 each independently represent —C—;

wherein R c is in the ortho position;

wherein the R c , R d , and R e substitutions are each independently chosen from:

i) halogen;

ii) hydroxyl;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heterocyclic;

vi) substituted or unsubstituted heteroaryl;

vii) substituted or unsubstituted aryl;

viii) amino;

ix) mono-C 1 -C 4 alkylamino;

x) di-C 1 -C 4 alkylamino;

xi) nitro; and

xii) cyano,

wherein the compound is not 2,5-dimethoxy-N-(quinolin-3-yl)benzene-sulfonamide;

2-methoxy-5-methyl-N-(pyridine-3-yl)benzenesulfonamide;

2-ethoxy-5-methyl-N-(pyridine-3-yl)benzenesulfonamide; or

N-[(3-1H-1,2,4,-triazol-3-ylthio)-4-hydroxyphenyl]-2,5-dimethoxybenzenesulfonamide; and

wherein the compounds are TNAP inhibitors.

2. The method of claim 1 , wherein the compound has one of the following formula:

wherein further the substitutions are each independently chosen from:

i) halogen;

ii) hydroxyl;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heterocyclic;

vi) substituted or unsubstituted heteroaryl;

vii) substituted or unsubstituted aryl;

viii) amino;

ix) mono-C 1 -C 4 alkylamino;

x) di-C 1 -C 4 alkylamino;

xi) nitro; and

xii) cyano.

3. The method of claim 2 , wherein further the substitutions are each independently chosen from:

i) halogen;

ii) hydroxyl;

iii) C 1 -C 4 alkyl;

iv) C i -C 4 alkoxy;

v) substituted or unsubstituted heterocyclic;

vi) substituted or unsubstituted heteroaryl;

vii) substituted or unsubstituted aryl; and

viii) nitro.

4. The method of claim 3 , wherein further the substitutions are each independently chosen from:

i) hydroxyl;

ii) halogen;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heteroaryl; and

vi) nitro.

5. A method of inhibiting or reducing the severity or incidence of vascular calcification in a subject, comprising administering one or more compounds having one of the following formula:

wherein A 2 represents —N—;

wherein A 1 , A 3 , A 4 , A 5 , A 6 , and A 7 each independently represent —C—;

wherein R c is in the ortho position;

wherein the R b , R c , R d , and R e substitutions are each independently chosen from:

i) halogen;

ii) hydroxyl;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heterocyclic;

vi) substituted or unsubstituted heteroaryl;

vii) substituted or unsubstituted aryl;

viii) amino;

ix) mono-C 1 -C 4 alkylamino;

x) di-C 1 -C 4 alkylamino;

xi) nitro; and

xii) cyano,

wherein the compound is not 2,5-dimethoxy-N-(quinolin-3-yl)benzene-sulfonamide;

2-methoxy-5-methyl-N-(pyridine-3-yl)benzenesulfonamide;

2-ethoxy-5-methyl-N-(pyridine-3-yl)benzenesulfonamide; or

N-[(3-1H-1,2,4,-triazol-3-ylthio)-4-hydroxyphenyl]-2,5 -dimethoxybenzenesulfonamide; and

wherein the compounds are TNAP inhibitors.

6. The method of claim 5 , wherein the compound has one of the following formula:

wherein further the substitutions are each independently chosen from:

i) halogen;

ii) hydroxyl;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heterocyclic;

vi) substituted or unsubstituted heteroaryl;

vii) substituted or unsubstituted aryl;

viii) amino;

ix) mono-C 1 -C 4 alkylamino;

x) di-C 1 -C 4 alkylamino;

xi) nitro; and

xii) cyano.

7. The method of claim 6 , wherein further the substitutions are each independently chosen from:

i) halogen;

ii) hydroxyl;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heterocyclic;

vi) substituted or unsubstituted heteroaryl;

vii) substituted or unsubstituted aryl; and

viii) nitro.

8. The method of claim 7 , wherein further the substitutions are each independently chosen from:

i) hydroxyl;

ii) halogen;

iii) C 1 -C 4 alkyl;

iv) C 1 -C 4 alkoxy;

v) substituted or unsubstituted heteroaryl; and

vi) nitro.

9. The method of claim 1 , wherein administration of one or more compounds retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.

10. The method of claim 2 , wherein administration of one or more compounds retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.

11. The method of claim 1 , wherein R c is ortho-methoxy.

12. The method of claim 11 , wherein the compound has the formula:

13. The method of claim 5 , wherein R c is ortho-methoxy.

14. The method of claim 13 , wherein the compound has the formula: