Table 1.

IC₅₀ values against recombinant human soluble epoxide hydrolase and non-compartmental pharmacokinetic parameters after oral administration of sEH inhibitors in dogs (n=1).

Text #	Structure		HsEH IC50b (nM)	AUCc (uM*min)	T1/2d (h)	Teffe (h)	C24/IC50f
	La	R1a
1			3.2	3.1	2.9	3	<0.1
2			0.8	< LODg	-	-	-
3			14.1	2.4	1.0	0.5	<0.1
4			1.4	0.6	6.2	1	<0.1
5			9.0	< LOD	-	-	-
6			2.5	< LOD	-	-	-
7			5.1	< LOD	-	-	-
8			7.3	8.9	1.7	6	<0.1
9			2.4	< LOD	-	-	-
10			5.9	< LOD	-	-	-
11			2.1	< LOD	-	-	-
12			3.9	1.7	1.2	6	<0.1
13			0.8	< LOD	-	-	-
14			14.5	36	1.4	5	<0.1
15			3.2	5.6	1.6	6	<0.1
16			1.7	2.6	1.7	6	<0.1
17			1.4	4.9	2.0	8	<0.1
18			0.9	5.4	3.6	8	<0.1
19			2.6	2.6	1.8	4	<0.1
20			2.7	< LOD	-	-	-
21			1.3	< LOD	-	-	-
22			1.2	4.8	0.8	5	<0.1
23			1.1	< LOD	-	-	-
24			11.5	390	>24	>24	6.0
25			3.7	600	14	>24	51
26			2.1	260	15	>24	36
27			2.9	1700	>24	>24	130
28			10.2	< LOD	-	-	-
29			0.4	< LOD	-	-	-
30			0.8	< LOD	-	-	-
31			27.6	220	5.2	24	1.0
32			2.3	160	2.8	8	0.8
33			1.6	2.0	1.6	6	<0.1
34			1.8	8.0	2.2	8	<0.1
35			6.6	< LOD	-	-	-
36			0.4	1.2	3.2	8	<0.1
37			0.4	< LOD	-	-	-
38			4.8	13.7	6.1	8	<0.1
39			1.5	240	19	>24	46
40			1.3	290	>24	>24	51
41			8.1	17.4	7.3	8	<0.1
42			3.8	4.0	1.2	2	<0.1
43			6.1	< LOD	-	-	-
44			1.4	29.8	9.3	>24	5.1
45			0.6	240	>24	>24	86
46			2.8	0.7	1.5	1	<0.1
47			1.2	31.2	6.6	>24	3.9
48			0.4	19.2	3.5	>24	12
49			5.8	< LOD	-	-	-
50			0.8	< LOD	-	-	-
51			11.6	< LOD	-	-	-
52			1.8	10.2	5.4	8	0.5
53			3.3	6.7	5.3	8	0.2
54			11.3	< LOD	-	-	-
55			23.6	< LOD	-	-	-
56			4.7	5.9	2.3	5	<0.1
57			3.1	5.1	3.2	5	<0.1
58			1.5	1.4	5.3	3	<0.1
59			0.9	< LOD	-	-	-
60			5.1	< LOD	-	-	-
61			0.8	< LOD	-	-	-
62			2.8	12.6	7.9	8	0.7
63			71.4	< LOD	-	-	-
64			0.9	11.3	5.1	8	<0.1
65			5.2	< LOD	-	-	-
66			24.6	< LOD	-	-	-
67			28.7	< LOD	-	-	-
68			13.6	< LOD	-	-	-
69			12.2	8.5	4.5	4	<0.1
70			94.6	< LOD	-	-	-
71			39.9	<LOD	-	-	-
72			274	5.8	1.0	0	<0.1
73			28.3	<LOD	-	-	-
74			13	1.8	0.5	2	<0.1

^aR1= non-polar substituent: 1-adamantyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, cycloheptyl. L= linker: n-alkyl, piperidyl, cyclohexyloxy, phenyl. P= varied polar functional group or putative secondary pharmacophore. R₂= varied substituent.

^bIC₅₀ determined by fluorescent assay with recombinant human enzyme.

^carea under the curve (Time_0-infinite) obtained from non-compartmental analysis.

^dterminal half-life.

^etime of inhibitor concentration in vivo above IC₅₀ determined with human recombinant sEH.

^fratio of blood concentration over the IC₅₀ determined with recombinant human sEH after 24 hour.

^gunder the limit of detection (Table S1).