INHIBITORS OF EPOXIDE HYDROLASES FOR THE TREATMENT OF HYPERTENSION
The invention provides compounds that inhibit epoxide hydrolase in therapeutic applications for treating hypertension. A preferred class of compounds for practicing the invention have the structure shown by Formula 1 wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4 is hydrogen, R 2 is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4 is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1 and R 3 is each independently C 1 -C 20 substituted or unsubstituted alkyl, cycloalkyl, aryl, acyl, or heterocyclic.
1 . A method of treating hypertension in a patient, the method comprising administering to the patient a therapeutically effective amount of a nucleic acid which inhibits epoxide hydrolase (EH) gene expression.
2 . A method of claim 1 , wherein the nucleic acid is complementary to a portion of a human gene encoding EH.
3 . A method of claim 1 , wherein the nucleic acid is DNA.
4 . A method of claim 1 , wherein the nucleic acid is RNA.
5 . A method of claim 1 , wherein the nucleic acid is modified to increase resistance to nucleases.
6 . A method of delivering a reactive functionality to epoxide hydrolase, said method comprising contacting said epoxide hydrolase with a compound selected from the group consisting of Formula I and of Formula II, wherein
(a) compounds of Formula I have the structure
wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4 is hydrogen, R 2 is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4 is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1 and R 3 are each independently a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, acyl, or heterocyclic, and
(b) compounds of Formula II have the structure
wherein R is alkyl or aryl, the compound is trans- across the epoxide ring, OX is a carbonyl (═O) or hydroxy group (OH) and R′ is a H, alkyl or aryl group,
and further wherein said compound of Formula I or Formula II is derivatized with a reactive functionality.
7 . A method of claim 6 , wherein the reactive functionality is an alkylating agent or a Michael acceptor
8 . A method of claim 7 , wherein the alkylating agent is a halogen.
9 . A method of claim 7 , wherein the alkylating agent is an epoxide.
10 . A method of claim 6 , wherein said compound of Formula I or Formula II is derivatized with a Michael acceptor.
11 . A method of claim 6 , wherein said compound is a compound of Formula I.
12 . A method of claim 6 , wherein said compound is a compound of Formula II.
13 . A method of detecting epoxide hydrolase, said method comprising contacting said epoxide hydrolase with a compound selected from the group consisting of Formula I and of Formula II, wherein
(a) compounds of Formula I have the structure
wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4 is hydrogen, R 2 is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4 is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1 and R 3 are each independently a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, acyl, or heterocyclic, and
(b) compounds of Formula II have the structure
wherein R is alkyl or aryl, the compound is trans- across the epoxide ring, OX is a carbonyl (═O) or hydroxy group (OH) and R′ is a H, alkyl or aryl group,
and further wherein said compound of Formula I or Formula II is derivatized with a fluorescent or affinity label.