Inhibitors for the soluble epoxide hydrolase

Abstract

Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases.

1 . A method for inhibiting a soluble epoxide hydrolase, comprising contacting said soluble epoxide hydrolase with an inhibiting amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 1  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         2 . A method for inhibiting a soluble epoxide hydrolase, comprising contacting said soluble epoxide hydrolase with an inhibiting amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         3 . The method in accordance with  claim 1 , wherein R 1  is selected from the group consisting of C 5 -C 12  cycloalkyl, phenyl and naphthyl.  
     
     
         4 . The method in accordance with  claim 1 , wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—.  
     
     
         5 . The method in accordance with  claim 1 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; P 2  is selected from the group consisting of —C(O)O—, —CH(OH)—, —OC(O)—, —C(O)NH— and —NHC(O)—; m is 0 and L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene.  
     
     
         6 . The method in accordance with  claim 1 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; P 2  is selected from the group consisting of —C(O)O—, —OC(O)—, —C(O)NH— and —NHC(O)—; n and m are each 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         7 . The method in accordance with  claim 1 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; n is 0; m is 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         8 . The method in accordance with  claim 1 , wherein said compound has formula (II) wherein A 1  is a dipeptide or dipeptide analog.  
     
     
         9 . The method in accordance with  claim 8 , wherein A 1  is a dipeptide having an N-terminal residue selected from the group consisting of Tyr, His, Lys, Phe and Trp, and a C-terminal residue selected from the group consisting of Ala, Arg, Asp, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.  
     
     
         10 . The method in accordance with  claim 1 , wherein m is 1 and P 3  is selected from those groups that reduce metabolism by esterase dependent inactivation, beta-oxidation, P450-dependent omega hydroxylation or by inhibiting P450 omega hydroxylase.  
     
     
         11 . The method in accordance with  claim 2 , wherein R 1  is selected from the group consisting of C 5 -C 12  cycloalkyl, phenyl and naphthyl.  
     
     
         12 . The method in accordance with  claim 2 , wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—.  
     
     
         13 . The method in accordance with  claim 2 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; P 2  is selected from the group consisting of —C(O)O—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —OC(O)—, —C(O)NH— and —NHC(O)—; m is 0 and L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, and substituted or unsubstituted arylene.  
     
     
         14 . The method in accordance with  claim 2 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; P 2  is selected from the group consisting of —C(O)O—, —O(CH 2 CH 2 O) q —, —OC(O)—, —C(O)NH— and —NHC(O)—; n and m are each 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, and substituted or unsubstituted arylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         15 . The method in accordance with  claim 2 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; n is 0; m is 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, and substituted or unsubstituted arylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         16 . The method in accordance with  claim 2 , wherein m is 1 and P 3  is selected from those groups that reduce metabolism by esterase dependent inactivation, beta-oxidation, P450-dependent omega hydroxylation or by inhibiting P450 omega hydroxylase.  
     
     
         17 . A method for inhibiting a soluble epoxide hydrolase, comprising contacting said soluble epoxide hydrolase with an inhibiting amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         18 . A method of treating diseases modulated by soluble epoxide hydrolases, said method comprising administering to a subject in need of such treatment an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         19 . The method in accordance with  claim 18 , wherein said disease is selected from the group consisting of hypertension, inflammation, adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome and arthritis.  
     
     
         20 . The method in accordance with  claim 19 , wherein said hypertension is selected from the group consisting of renal hypertension, pulmonary hypertension and hepatic hypertension.  
     
     
         21 . The method in accordance with  claim 19 , wherein said inflammation is selected from the group consisting of renal inflammation, vascular inflammation, and lung inflammation.  
     
     
         22 . A method of treating diseases modulated by soluble epoxide hydrolases, said method comprising administering to a subject in need of such treatment an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2   , —NHS(O)   2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         23 . The method in accordance with  claim 22 , wherein said disease is selected from the group consisting of hypertension, inflammation, adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome and arthritis.  
     
     
         24 . The method in accordance with  claim 23 , wherein said hypertension is selected from the group consisting of renal hypertension, pulmonary hypertension and hepatic hypertension.  
     
     
         25 . The method in accordance with  claim 23 , wherein said inflammation is selected from the group consisting of renal inflammation, vascular inflammation, and lung inflammation.  
     
     
         26 . A method of treating diseases modulated by soluble epoxide hydrolases, said method comprising administering to a subject in need of such treatment an effective amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         27 . The method in accordance with  claim 26 , wherein said disease is selected from the group consisting of hypertension, inflammation, adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome and arthritis.  
     
     
         28 . The method in accordance with  claim 27 , wherein said hypertension is selected from the group consisting of renal hypertension, pulmonary hypertension and hepatic hypertension.  
     
     
         29 . The method in accordance with  claim 27 , wherein said inflammation is selected from the group consisting of renal inflammation, vascular inflammation, and lung inflammation.  
     
     
         30 . A method for reducing renal deterioration in a subject, said method comprising administering to said subject an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 22 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 1 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof, and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         31 . The method in accordance with  claim 30 , wherein said renal deterioration is present in said subject afflicted with diabetes, hypertension or an inflammatory disorder.  
     
     
         32 . A method for reducing renal deterioration in a subject, said method comprising administering to said subject an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         33 . The method in accordance with  claim 32 , wherein said renal deterioration is present in said subject afflicted with diabetes, hypertension or an inflammatory disorder.  
     
     
         34 . A method for reducing renal deterioration in a subject, said method comprising administering to said subject an effective amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         35 . The method in accordance with  claim 34 , wherein said renal deterioration is present in said subject afflicted with diabetes, hypertension or an inflammatory disorder.  
     
     
         36 . A method for inhibiting progression of nephropathy in a subject, said method comprising administering to said subject an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of-C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 22 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 1 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         37 . The method in accordance with  claim 36  wherein the subject is (a) a person with diabetes mellitus whose blood pressure is 130/85 or less, (b) a person with metabolic syndrome whose blood pressure is 130/85 or less, (c) a person with a triglyceride level over 215 mg/dL, or (d) a person with a cholesterol level over 200 mg/dL.  
     
     
         38 . A method for inhibiting progression of nephropathy in a subject, said method comprising administering to said subject an effective amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         39 . The method in accordance with  claim 38  wherein the subject is (a) a person with diabetes mellitus whose blood pressure is 130/85 or less, (b) a person with metabolic syndrome whose blood pressure is 130/85 or less, (c) a person with a triglyceride level over 215 mg/dL, or (d) a person with a cholesterol level over 200 mg/dL.  
     
     
         40 . A method for reducing blood pressure in a subject, said method comprising administering to said subject an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         41 . The method in accordance with  claim 40 , said method further comprising administering to said subject an effective amount of a cis-epoxyeicosantrienoic acid.  
     
     
         42 . The method in accordance with  claim 41 , wherein said cis-epoxyeicosantrienoic acid is administered with said compound having formula (I) or (II).  
     
     
         43 . A method for reducing blood pressure in a subject, said method comprising administering to said subject an effective amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         44 . The method in accordance with  claim 43 , said method further comprising administering to said subject an effective amount of a cis-epoxyeicosantrienoic acid.  
     
     
         45 . The method in accordance with  claim 44 , wherein said cis-epoxyeicosantrienoic acid is administered with said compound having formula (I) or (II).  
     
     
         46 . A method of inhibiting the proliferation of vascular smooth muscle cells in a subject, said method comprising administering to said subject an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 22 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         47 . A method of inhibiting the proliferation of vascular smooth muscle cells in a subject, said method comprising administering to said subject an effective amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         48 . A method of inhibiting the progression of obstructive pulmonary disease, an interstitial lung disease, or asthma in a subject, said method comprising administering to said subject an effective amount of a compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         49 . The method in accordance with  claim 48 , wherein said obstructive pulmonary disease is selected from the group consisting of chronic obstructive pulmonary disease, emphysema, and chronic bronchitis.  
     
     
         50 . The method in accordance with  claim 48 , wherein said interstitial lung disease is idiopathic pulmonary fibrosis or is one associated with exposure to dust.  
     
     
         51 . The method in accordance with  claim 48 , said method further comprising administering to said subject an effective amount of a cis-epoxyeicosantrienoic acid.  
     
     
         52 . The method in accordance with  claim 51 , wherein said cis-epoxyeicosantrienoic acid is administered with said compound having formula (I) or (II).  
     
     
         53 . A method of inhibiting the progression of obstructive pulmonary disease, an interstitial lung disease, or asthma in a subject, said method comprising administering to said subject an effective amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         54 . The method in accordance with  claim 53 , wherein said obstructive pulmonary disease is selected from the group consisting of chronic obstructive pulmonary disease, emphysema, and chronic bronchitis.  
     
     
         55 . The method in accordance with  claim 53 , wherein said interstitial lung disease is idiopathic pulmonary fibrosis or is one associated with exposure to dust.  
     
     
         56 . The method in accordance with  claim 53 , said method further comprising administering to said subject an effective amount of a cis-epoxyeicosantrienoic acid.  
     
     
         57 . The method in accordance with  claim 56 , wherein said cis-epoxyeicosantrienoic acid is administered with said compound having formula (I) or (II).  
     
     
         58 . A compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         59 . A compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts, wherein 
 R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, aryl, heteroaryl and combinations thereof, wherein said cycloalkyl portions are monocyclic or polycyclic;  
 P 1  is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —CH 2 C(O)NH—, —C(O)NH— and —NHC(O)—;  
 P 2  is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;  
 P 2a  is selected from the group consisting of —C(O)— and —NHC(O)—;  
 P 3  is a tertiary pharmacophore selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 1 , —C(O)NHS(O) 2 R 1 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl;  
 the subscripts n and m are each independently 0 or 1, and at least one of n or m is 1, and the subscript q is 0 to 3;  
 L 1  is a first linker selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene;  
 L 2  is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene, substituted and unsubstituted arylene, and combinations thereof; and  
 A 1  is a member selected from the group consisting of an amino acid, a dipeptide and a dipeptide analog.  
 
     
     
         60 . The compound in accordance with  claim 58 , wherein R 1  is selected from the group consisting of C 5 -C 12  cycloalkyl, phenyl and naphthyl.  
     
     
         61 . The compound in accordance with  claim 58 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; P 2  is selected from the group consisting of —C(O)O—, —CH(OH)—, —OC(O)—, —C(O)NH— and —NHC(O)—; n and m are each 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 1  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         62 . The compound in accordance with  claim 58 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; n is 0; m is 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         63 . The compound in accordance with  claim 58 , wherein said compound has formula (II) wherein A 1  is a dipeptide or dipeptide analog.  
     
     
         64 . The compound in accordance with  claim 58 , wherein said compound has formula (II) wherein A 1  is a dipeptide having an N-terminal residue selected from the group consisting of Tyr, His, Lys, Phe and Trp, and a C-terminal residue selected from the group consisting of Ala, Arg, Asp, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.  
     
     
         65 . The compound in accordance with  claim 59 , wherein R 1  is selected from the group consisting of C 5 -C 12  cycloalkyl, phenyl and naphthyl.  
     
     
         66 . The compound in accordance with  claim 59 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; P 2  is selected from the group consisting of —C(O)O—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —OC(O)—, —C(O)NH— and —NHC(O)—; n and m are each 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, and substituted or unsubstituted arylene; L 2  is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         67 . The compound in accordance with  claim 59 , wherein the compound has formula (I), wherein P 1  is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; n is 0; m is 1; L 1  is selected from the group consisting of unsubstituted C 2 -C 6  alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, and substituted or unsubstituted arylene; L2 is selected from the group consisting of substituted or unsubstituted C 2 -C 6  alkylene; and P 3  is selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl.  
     
     
         68 . The compound in accordance with  claim 59 , wherein-the compound has formula (I) wherein R 1  is a member selected from the group consisting of C 5 -C 12  cycloalkyl, wherein said cycloalkyl portions are monocyclic or polycyclic; P 1  is selected from the group consisting of —NHC(O)NH—; P 2  is selected from the group consisting of —O(CH 2 CH 2 O) q — and —C(O)O—; P 3  is selected from the group consisting of C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, —NHS(O) 2 R 2 , —C(O)OR 2  and carboxylic acid analogs, wherein R 2  is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4  alkyl; m is 1 and q is 0 to 3; L 1  is selected from the group consisting of substituted and unsubstituted C 2 -C 6  alkylene, substituted and unsubstituted C 3 -C 6  cycloalkylene, and substituted or unsubstituted arylene; and L 2  is selected from the group consisting of substituted and unsubstituted C 2 -C 12  alkylene.  
     
     
         69 . A compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         70 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 58 .  
     
     
         71 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 59 .  
     
     
         72 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 69 .  
     
     
         73 . A method for stabilizing biologically active epoxides in the presence of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound of  claim 58 , sufficient to inhibit the activity of said soluble epoxide hydrolase and stabilize said biologically active epoxide.  
     
     
         74 . A method for stabilizing biologically active epoxides in the presence of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound of  claim 59 , sufficient to inhibit the activity of said soluble epoxide hydrolase and stabilize said biologically active epoxide.  
     
     
         75 . A method for stabilizing biologically active epoxides in the presence of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         76 . The method in accordance with  claim 73 , wherein said contacting is conducted in an in vitro assay.  
     
     
         77 . The method in accordance with  claim 73 , wherein said contacting is conducted in vivo.  
     
     
         78 . The method in accordance with  claim 74 , wherein said contacting is conducted in an in vitro assay.  
     
     
         79 . The method in accordance with  claim 74 , wherein said contacting is conducted in vivo.  
     
     
         80 . The method in accordance with  claim 75 , wherein said contacting is conducted in an in vitro assay.  
     
     
         81 . The method in accordance with  claim 75 , wherein said contacting is conducted in vivo.  
     
     
         82 . The method for reducing the formation of a biologically active diol produced by the action of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound of  claim 58 , sufficient to inhibit the activity of said soluble epoxide hydrolase and reduce the formation of said biologically active diol.  
     
     
         83 . The method for reducing the formation of a biologically active diol produced by the action of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound of  claim 59 , sufficient to inhibit the activity of said soluble epoxide hydrolase and reduce the formation of said biologically active diol.  
     
     
         84 . A method for reducing the formation of a biologically active diol produced by the action of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         85 . The method in accordance with  claim 82 , wherein said contacting is conducted in an in vitro assay.  
     
     
         86 . The method in accordance with  claim 82 , wherein said contacting is conducted in vivo.  
     
     
         87 . The method in accordance with  claim 83 , wherein said contacting is conducted in an in vitro assay.  
     
     
         88 . The method in accordance with  claim 83 , wherein said contacting is conducted in vivo.  
     
     
         89 . The method in accordance with  claim 84 , wherein said contacting is conducted in an in vitro assay.  
     
     
         90 . The method in accordance with  claim 84 , wherein said contacting is conducted in vivo.  
     
     
         91 . A method for monitoring the activity of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound of  claim 58  sufficient to produce a detectable change in fluorescence of said soluble epoxide hydrolase by interacting with one or more tryptophan residues present in the catalytic site of said sEH.  
     
     
         92 . A method for monitoring the activity of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound of  claim 59  sufficient to produce a detectable change in fluorescence of said soluble epoxide hydrolase by interacting with one or more tryptophan residues present in the catalytic site of said sEH.  
     
     
         93 . A method for monitoring the activity of a soluble epoxide hydrolase, said method comprising contacting said soluble epoxide hydrolase with an amount of a compound having the formula described in Tables 1-18 and their pharmaceutically acceptable salts.  
     
     
         94 . The method in accordance with  claim 92 , wherein said compound has an aryl group present one or more components selected from the group consisting of R 1 , L 2 , P 3  and A 1 .