Myosin light chain kinase inhibitor compounds, compositions and related methods of use

1. A method of inhibiting myosin light chain kinase activity, said method comprising:

providing a medium comprising a myosin light chain kinase; and

contacting said medium with a compound of a formula

wherein R 3 is selected from H and alkyl moieties; R 6 is selected from H, halo, alkyl, aryl and heterocyclic moieties; n is an integer from 8 to 14; and X is (CH 2 ) 2 Y, where Y is selected from substituted and unsubstituted pyrrolidinyl, substituted and unsubstituted pyrrolyl, substituted and unsubstituted pyrazolyl, substituted and unsubstituted imidazolyl and substituted and unsubstituted cyclopentyl moieties; and salts thereof, said compound in an amount sufficient to at least partially inhibit said kinase activity.

2. The method of claim 1 wherein said contact is in vivo.

3. The method of claim 2 contacting at least one of epithelial and endothelial tissue exhibiting barrier dysfunction.

4. The method of claim 3 wherein the at least one of epithelial and endothelial tissue exhibiting barrier dysfunction that is contacted is injured pulmonary tissue.

5. The method of claim 3 wherein said compound is in a pharmaceutical composition.

6. The method of claim 1 wherein R 3 is hydrogen, R 6 is halo or phenyl, n is 10, and X is selected from 6-phenylpyridazin-3-yl, 1H-imidazol-2-yl methyl, 1-methylpyrrolidin-2-yl methyl, pyrrolidin-2-yl methyl and cyclopentyl methyl.

7. The method of claim 6 wherein the compound is selected from:

11-(6-imino-3-phenylpyridazin-1(6H)-yl)-N-(6-phenylpyridazin-3-yl)undecanamide;

11-(3-chloro-6-iminopyridazin-1(6H)-yl)-N-(6-phenylpyridazin-3-yl)undecanamide;

N-((1H-imidazol-2-yl)methyl)-11-(6-imino-3-phenylpyridazin-1(6H)-yl)undecanamide;

11-(6-imino-3-phenylpyridazin-1(6H)-yl)-N-((1-methylpyrrolidin-2-yl)methyl)undecanamide;

11-(6-imino-3-phenylpyridazin-1(6H)-yl)-N-(pyrrolidin-2-ylmethyl)undecanamide; and

N-(cyclopentylmethyl)-11-(6-imino-3-phenylpyridazin-1(6H)-yl)undecanamide.

8. A method of treating progression of acute tissue injury, said method comprising:

providing at least one of epithelial and endothelial tissue with barrier dysfunction, and

contacting said tissue with a compound of a formula

wherein R 3 is selected from H and alkyl moieties; R 6 is selected from H, halo, alkyl, aryl and heterocyclic moieties; n is an integer from 8 to 14; and X is (CH 2 ) 2 Y, where Y is selected from substituted and unsubstituted pyrrolidinyl, substituted and unsubstituted pyrrolyl, substituted and unsubstituted pyrazolyl, substituted and unsubstituted imidazolyl and substituted and unsubstituted cyclopentyl moieties; and salts thereof, said compound in a therapeutically sufficient amount.

9. The method of claim 8 wherein said contact is in vivo.

10. The method of claim 9 wherein the at least one of epithelial and endothelial tissue exhibiting barrier dysfunction that is contacted is injured pulmonary tissue.

11. The method of claim 9 wherein said therapeutic amount is selective for MLCK inhibition over inhibition of at least one of DAPK, PKC and PKA.

12. The method of claim 11 wherein said MLCK inhibition is confirmed against MLCK210 (KO) mice.

13. The method of claim 8 wherein R 3 is hydrogen, R 6 is halo or phenyl, n is 10, and X is selected from 6-phenylpyridazin-3-yl, 1H-imidazol-2-yl methyl, 1-methylpyrrolidin-2-yl methyl, pyrrolidin-2-yl methyl and cyclopentyl methyl.

14. The method of claim 13 wherein the compound is selected from:

11-(6-imino-3-phenylpyridazin-1(6H)-yl)-N-(6-phenylpyridazin-3-yl)undecanamide;

11-(3-chloro-6-iminopyridazin-1(6H)-yl)-N-(6-phenylpyridazin-3-yl)undecanamide;

N-((1H-imidazol-2-yl)methyl)-11-(6-imino-3-phenylpyridazin-1(6H)-yl)undecanamide;

11-(6-imino-3-phenylpyridazin-1(6H)-yl)-N-((1-methylpyrrolidin-2-yl)methyl)undecanamide;

11-(6-imino-3-phenylpyridazin-1(6H)-yl)-N-(pyrrolidin-2-ylmethyl)undecanamide; and

N-(cyclopentylmethyl)-11-(6-imino-3-phenylpyridazin-1(6H)-yl)undecanamide.

15. A method for selective kinase inhibition, said method comprising:

providing a pyridazinylalkaneamide compound of a formula

wherein R 3 is selected from H and alkyl moieties; R 6 is selected from H, halo, alkyl, aryl and heterocyclic moieties; n is an integer from 8 to 14; and X is (CH 2 ) 2 Y, where Y is selected from substituted and unsubstituted pyrrolidinyl, substituted and unsubstituted pyrrolyl, substituted and unsubstituted pyrazolyl, substituted and unsubstituted imidazolyl and substituted and unsubstituted cyclopentyl moieties; and

contacting said compound with a medium comprising a myosin light chain kinase, said compound in an amount sufficient to at least partially inhibit said kinase activity, said X moiety providing said compound inhibition activity selective over at least one of death-associated protein kinase, protein kinase A and protein kinase C.

16. The method of claim 15 wherein said X moiety provides said compound an aqueous solubility of log S about ≦−3.