The cytochrome P450 eicosanoid 14 15 8 11 acid (14 15 is a powerful endogenous autacoid that has been ascribed an impressive array of physiologic functions including regulation of blood pressure. inhibition of soluble epoxide hydrolase (sEH). Tetrazole 19 (ED50 0.18 μM) and oxadiazole-5-thione 25 (ED50 0.36 μM) were 12- and 6-fold more potent respectively than 14 15 as vasorelaxants; on the other hand their ability to block sEH differed substantially i.e. 11 vs >500 nM. These data will expedite the development of potent and specific in vivo drug candidates. Introduction An imposing body of studies 1 spanning more than three decades has cogently elucidated the involvement of epoxyeicosatrienoic acids (EETs) in a wide array of critical physiological functions inter alia blood pressure regulation 2 nociception 3 adipogenesis 4 anti-inflammatory activity 5 Rabbit Polyclonal to Caspase 2 (p18, Cleaved-Thr325). organ regeneration 6 insulin potentiation 7 podocyte integrity 8 and cellular responses to bacterial infection.9 The most prominent regioisomer 10 14 15 8 Hz 2 1.98 (m 4 1.7 (m 2 1.24 (m 16 0.9 (t = 7.6 Hz 3 Levonorgestrel 13 NMR (CD3OD 75 MHz) δ 160.16 156.81 129.77 129.47 39.81 39.68 29.88 29.8 29.35 28.99 28.69 Levonorgestrel 28.55 27.48 26.85 26.81 26.68 22.96 22.31 13.22 HRMS calcd for C19H37N6O [M + 1]+ 365.3029 found 365.3030. = 7.5 Hz 2 1.98 (m 4 1.21 (m 16 0.92 (t = 7.3 Hz 3 13 NMR (100 MHz) δ 160.12 160.08 153.31 130.62 129.46 39.93 39.85 31.35 29.33 28.94 28.89 28.68 27.02 26.84 26.69 23.96 20.23 13.9 HRMS calcd for C19H35N4O4S [M + 1]+ 415.2379 found 415.2372. 12 6.4 Hz 4 2.08 (m 4 1.5 (m 4 1.4 (m 10 1.04 (s 9 13 NMR (100 MHz) δ 135.81 Levonorgestrel 134.4 130.61 129.71 129.6 127.8 64.21 63.14 32.78 32.6 29.98 29.27 27.42 27.14 27.1 26.08 25.92 19.48 HRMS calcd for C28H43O2Si [M + 1]+ 439.3032 found 439.3027. 1 5.8 Hz Levonorgestrel 2 3.27 (t = 6.3 Hz 2 1.96 (m 4 1.24 (m 12 1.04 (s 9 13 NMR (100 MHz) δ 135.84 134.41 130.93 129.75 129.12 127.83 64.22 51.62 32.81 29.93 29.3 28.68 27.46 27.14 27.02 26.9 25.96 19.49 IR (neat) 2930 2783 2331 2097 1106 cm-1. HRMS calcd for C28H42N3OSi [M + 1]+ 464.3097 found 464.3099 1 5.2 Hz 2 2.62 (t = 4.8 Hz 2 1.92 (m 4 1.4 (m 4 1.2 (m 8 1.03 (s 9 13 NMR (100 MHz) δ 135.79 134.37 130.42 129.7 127.78 64.19 42.28 33.44 32.77 29.93 29.28 27.4 27.21 27.1 25.92 19.44 HRMS calcd for C28H44NOSi [M + 1]+ 438.3192 found 438.3186. 1 6.5 Hz 2 3.08 (m 4 1.96 (m 4 1.22 (m 18 1.02 (s 9 0.89 (t = 7.3 Hz 3 13 NMR (100 MHz) δ 159.23 135.8 134.24 130.52 129.74 129.49 127.82 64.22 40.62 40.54 32.8 30.33 29.95 29.37 29.32 27.46 27.34 27.18 27.11 25.97 22.71 19.46 14.29 HRMS calcd for C34H55N2O2Si [M + 1 551.4033 found 551.4032. 1 6.5 Hz 2 3.08 (m 4 1.96 (m 4 1.22 (m 18 0.88 (t = 7.0 Hz 3 13 NMR (125 MHz) δ 159.26 130.23 129.62 63.72 40.33 40.29 32.92 30.3 30.26 29.74 29.35 29.13 27.26 27.2 27.13 25.82 22.69 14.27 HRMS calcd for C18H37N2O2 [M + 1]+ 313.2855 found 313.2857. 1 9.3 Hz 2 3.1 (m 4 1.98 (m 4 1.8 (m 2 1.25 (m 16 0.92 (t = 7.2 Hz 3 13 NMR (100 MHz) δ 159.51 130.14 129.69 40.48 40.39 34.2 32.96 30.34 29.67 29.36 28.58 28.25 27.31 27.27 27.17 22.68 14.26 HRMS calcd for C18H36BrN2O [M + 1]+ 375.2011 found 375.2014. 1 7 Hz 2 1.98 (m 4 1.24 (m 18 0.89 (t = 7.0 Hz 3 13 NMR (125 MHz) δ 159.41 129.94 129.86 120.14 40.45 40.35 30.3 29.5 29.33 28.7 28.51 27.26 27.16 25.47 22.66 17.28 14.24 IR (neat) 2930 2281 2184 2042 1936 1613 1197 1042 cm-1. HRMS calcd for C19H36N3O [M + 1 322.2858 found 322.2867. = 3.9 Hz 2 3.31 (q = 5.2 Hz 4 1.96 (m 4 1.5 (m 6 1.22 (m 10 1.06 (s 9 0.92 (t = 7.8 Hz 3 13 NMR (100 MHz) δ 160.33 135.8 134.35 130.73 129.74 129.2 127.83 64.17 39.89 39.69 32.79 31.48 29.94 29.29 29.07 27.46 27.23 27.14 27 25.96 20.29 19.46 13.96 HRMS calcd for C34H53N2O3Si [M + 1 565.3826 found 565.3824. = 4.2 Hz 2 3.26 (q = 5.6 Hz 4 2.17 (br s 1 1.95 (m 4 1.44 (m 6 1.2 (m 10 0.87 (t = 7.2 Hz 3 13 NMR (100 MHz) δ 160.15 130.66 129.21 62.98 39.8 39.63 32.93 31.39 29.77 29.18 28.95 27.26 27 26.88 25.8 20.18 13.85 HRMS calcd for Levonorgestrel C18H35N2O3 [M + 1]+ 327.2648 found 327.2648. = 6.4 Hz 2 3.22 (q = 7.2 Hz 4 1.9 (m 4 1.72 (m 2 1.42 (m 4 1.2 (m 10 0.85 (t = 7.3 Hz 3 13 NMR (100 MHz) δ 160.17 160.15 130.4 129.34 39.77 39.59 34.12 32.93 31.4 29.62 29 28.54 27.25 27.24 27 26.91 20.18 13.85 HRMS calcd for C18H34BrN2O2 [M + 1]+ 389.1804 found 389.1809. = 8.6 Hz 4 2.32 (t = 7.6 Hz 2 1.98 (m 4 1.3 (m 16 0.92 (t = 7.2 Hz 3 13 NMR (100 MHz) δ 160.03 (2C) 130.03 129.08 120.1 39.88 39.42 31.22 29.4 28.82 28.6 28.42 27.07 27.06 26.82 25.54 20.06 17.01 13.8 HRMS calcd for C19H34N3O2 [M + 1]+ 336.2651 found 336.2650. = 6.4 Hz 4 1.98 (m 6 1.5 (m 6 1.26 (m 10 0.92 (t = 7.3 Hz 3 13 NMR (CD3OD.