Inhibitors of Fatty Acid Amide Hydrolase
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14 3365
125 MHz) δ 187.9, 157.2, 153.2, 150.1, 146.2, 137.1, 126.8, 124.1,
120.3, 83.8, 68.7, 38.4, 27.7, 22.9, 18.2; IR (film) νmax 2938, 2867,
2115, 1698, 1603, 1575, 1505, 1470, 1426, 1385, 1283, 1245, 1127,
1086, 1024, 991, 962, 853, 785, 743 cm-1; ESI-TOF-MS m/z
255.1135 (C15H14N2O2 + H+ requires 255.1128).
explored. Amide placement in the side chain led to a dramatic
loss in inhibitory potency, whereas hydroxyl substitution at
positions 2 and 6 provided effective inhibitors (13a, 2-position
OH, Ki ) 8 nM). Just as importantly, proteome-wide selectivity
screening of the candidate inhibitors showed extraordinary
selectivity for FAAH over all other serine hydrolases and
proteases. Most notably, inhibitors that possess the side chain
conformational constraints (11a, 11e-11j) generally were very
selective for FAAH over KIAA1363 and typically 100-1000-
fold selective for FAAH over TGH. Finally and despite the
lipophilic and non-drug-like nature of the FAAH substrates, the
lead structure 2b and the potent inhibitors disclosed herein
including 5hh and 11j possess much more favorable drug-like
characteristics.80
A solution of 1-chloro-3-iodobenzene (49 mg, 0.205 mmol) in
anhydrous THF (0.5 mL) was treated with PdCl2(PPh3)2 (7 mg,
0.01 mmol). After the resulting solution was stirred for 5 min at
25 °C, Et3N (0.2 mL, 0.603 mmol) and CuI (10 mg, 0.053 mmol)
were added. The suspension was stirred for 35 min, and 3b
(30 mg, 0.067 mmol) was added. After being stirred for 14 h at
25 °C, the reaction mixture was filtered through Celite and
concentrated. PTLC (SiO2, 50% EtOAc-hexanes) afforded 1-oxo-
1-[5-(2-pyridyl)oxazol-2-yl]-7-(3-chlorophenyl)hept-6-yne (4hh; 24
mg, 0.066 mmol, 56%) as a yellow solid: mp 50-51 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82
(td, 1H, J ) 7.7, 1.8 Hz), 7.38 (m, 1H), 7.34-7.31 (m, 1H), 7.27-
7.18 (m, 3H), 3.20 (t, 2H, J ) 7.4 Hz), 2.49 (t 2H, J ) 7.0 Hz),
2.00-1.95 (m, 2H), 1.77-1.71 (m, 2H); 13C NMR (CDCl3, 125
MHz) δ 187.9, 157.2, 153.3, 150.1, 146.2, 137.1, 133.9, 131.4,
129.6, 129.3, 127.8, 126.8, 125.5, 124.1, 120.3, 90.9, 79.8, 38.5,
27.8, 23.1, 19.1; IR (film) νmax 3061, 2932, 2865, 2230, 1703, 1592,
1575, 1558, 1505, 1471, 1426, 1385, 1283, 1243, 1152, 1081, 1065,
1023, 990, 962, 930, 880, 784, 740, 683 cm-1; ESI-TOF-MS m/z
365.1058 (C21H17ClN2O4 + H+ requires 365.1051).
A solution of 4hh (15 mg, 0.041 mmol) in anhydrous THF
(1 mL) was treated with a catalytic amount of Raney nickel (washed
before use with THF). The reaction mixture was purged with H2
and stirred at 25 °C overnight. The suspension was filtered through
Celite and concentrated. The crude product was dissolved in
anhydrous CH2Cl2 (2 mL) and treated with Dess-Martin reagent
(29 mg, 0.068 mmol). After being stirred for 3 h at 25 °C, the
reaction mixture was quenched with saturated aqueous Na2CO3 and
saturated aqueous Na2S2O3. After being stirred for 15 min, the
mixture was extracted with CH2Cl2. The organic layer was dried
over Na2SO4, filtered, and concentrated. PTLC (SiO2, 40% EtOAc-
hexanes) afforded the title compound 5hh (10 mg, 0.027 mmol,
67%) as a white solid: mp 91-92 °C; 1H NMR (CDCl3, 600 MHz)
δ 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J ) 7.8,
1.4 Hz), 7.34-7.31 (m, 1H), 7.21-7.14 (m, 3H), 7.04 (d, 1H, J )
7.5 Hz), 3.11 (t, 2H, J ) 7.4 Hz), 2.59 (t, 2H, J ) 7.4 Hz), 1.81-
1.76 (m, 2H), 1.65-1.60 (m, 2H), 1.46-1.36 (m, 4H); 13C NMR
(CDCl3, 125 MHz) δ 188.4, 157.3, 153.2, 150.1, 146.3, 144.7,
137.1, 133.9, 129.5, 128.5, 126.8, 126.6, 124.1, 120.4, 39.0, 35.5,
31.0, 28.9, 28.8, 23.8; IR (film) νmax 2930, 2856, 1698, 1601, 1575,
1505, 1470, 1426, 1385, 1285, 1081, 1035, 990, 962, 935, 783,
741, 696 cm-1; ESI-TOF-MS m/z 369.1363 (C21H21ClN2O2 + H+
requires 369.1364).
1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(4-(benzyloxy)phenyl)-
propane (11a). 4-Hydroxycinnamic acid (700 mg, 4.26 mmol) was
dissolved in EtOAc (15 mL), and 10% Pd/C (51 mg, 0.479 mmol)
was added. The reaction mixture was stirred under an atmosphere
of H2 overnight at room temperature before it was filtered through
Celite and concentrated in vacuo. No further purification was needed
to yield 3-(4-hydroxyphenyl)propanoic acid (700 mg, 99%). A
solution of 3-(4-hydroxyphenyl)propanoic acid (700 mg, 4.21
mmol) in anhydrous DMF (16 mL) at 0 °C was treated with a
solution of 60% NaH (450 mg, 18.75 mmol) in DMF dropwise.
The reaction mixture was stirred for 10 min before benzyl bromide
(0.675 mL, 5.68 mmol) was added. The reaction mixture was stirred
overnight at room temperature, quenched with aqueous 1 N HCl,
and extracted with EtOAc. The combined organic layers were
washed with saturated aqueous NH4Cl and saturated aqueous NaCl
and dried over Na2SO4. Column chromatography (SiO2, 4 × 9 cm,
20-40% EtOAc-hexanes gradient) afforded 3-(4-(benzyloxy)-
phenyl)propanoic acid (780 mg, 72%) as a white solid: 1H NMR
(CDCl3, 500 MHz) δ 7.44 (d, 2H, J ) 7.4 Hz), 7.40 (t, 2H, J )
7.4 Hz), 7.35-7.32 (m, 1H), 7.14 (d, 2H, J ) 8.8 Hz), 6.92 (d,
2H, J ) 8.4 Hz), 5.06 (s, 2H), 2.92 (t, 2H, J ) 7.7 Hz), 2.66 (t,
2H, J ) 7.7 Hz); 13C NMR (CDCl3, 125 MHz) δ 179.0, 157.3,
137.0, 132.5, 129.2, 128.5, 127.9, 127.4, 114.9, 70.0, 35.8, 29.7.
Experimental Section
1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(3-chlorophenyl)hep-
tane (5hh). A solution of hept-6-ynoic acid (1.90 g, 14.8 mmol)
in anhydrous THF (90 mL) at -78 °C was treated with n-BuLi
(2.3 M in hexanes, 14.5 mL, 33.3 mmol). After the resulting solution
was stirred for 2 min, TMSCl (5.8 mL, 46.0 mmol) was added.
The reaction mixture was allowed to warm slowly to 25 °C and
was stirred for 1 h. The reaction was quenched with the addition
of aqueous 2 N HCl and extracted with CH2Cl2. The organic layer
was dried over Na2SO4, filtered, and concentrated. Column chro-
matography (SiO2, 4 × 6 cm, 20% EtOAc-hexanes) afforded
7-(trimethylsilyl)hept-6-ynoic acid (2.7 g, 13.6 mmol, 92%) as a
white solid: 1H NMR (CDCl3, 500 MHz) δ 2.40 (t, 2H, J ) 7.4
Hz), 2.24 (t, 2H, J ) 7.3 Hz), 1.78-1.72 (m, 2H), 1.62-1.56 (m,
2H), 0.15 (s, 9H).
A solution of 5-(2-pyridyl)oxazole72 (600 mg, 4.11 mmol) in
anhydrous THF (15 mL) at -78 °C was treated dropwise with a
solution of n-BuLi (2.2 M in hexanes, 2.4 mL, 4.52 mmol) under
N2, and the resulting solution was stirred at -78 °C for 20 min. A
solution of ZnCl2 (0.5 M in THF, 18 mL, 8.22 mmol) was added,
and the mixture was warmed to 0 °C. After the mixture was stirred
at 0 °C for 45 min, CuI (850 mg, 4.46 mmol) was added. After the
mixture was stirred at 0 °C for 10 min, a solution of 7-(trimeth-
ylsilyl)hept-6-ynoyl chloride (1.2 equiv, prepared from 7-(trimeth-
ylsilyl)hept-6-ynoic acid and oxalyl chloride) in anhydrous THF
(9 mL) was added dropwise, and the mixture was stirred at 0 °C
for an additional 1 h. The reaction mixture was diluted with a 1:1
mixture of hexanes and EtOAc (60 mL) and washed with 15%
aqueous NH4OH (2 × 30 mL), water (30 mL), and saturated
aqueous NaCl (30 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and evaporated. Column chromatography (SiO2,
4 × 6 cm, 30% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)-
oxazol-2-yl]-7-(trimethylsilyl)hept-6-yne (3a; 875 mg, 2.68 mmol,
74%) as a tan oil: 1H NMR (CDCl3, 400 MHz) δ 8.68 (m, 1H),
7.89-7.86 (m, 2H), 7.82 (td, 1H, J ) 7.6, 1.8 Hz), 7.34-7.31 (m,
1H), 3.15 (t, 2H, J ) 7.3 Hz), 2.30 (t, 2H, J ) 7.2 Hz), 1.94-1.86
(m, 2H), 1.68-1.60 (m, 2H), 0.14 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 187.9, 157.2, 153.2, 150.0, 146.1, 137.0, 126.8, 124.1,
120.3, 106.6, 84.8, 38.4, 27.9, 22.9, 19.6, 0.0; IR (film) νmax 2955,
2867, 2173, 1699, 1603, 1576, 1504, 1469, 1426, 1383, 1249, 1152,
1118, 1083, 1024, 929, 842, 784, 760 cm-1; ESI-TOF-MS m/z
327.1530 (C18H22N2O2Si + H+ requires 327.1523).
A solution of 3a (570 mg, 1.75 mmol, 1 equiv) in anhydrous
THF (6 mL) at 0 °C was treated with a solution of Bu4NF in THF
(1 M, 2.1 mL, 2.1 mmol). After being stirred for 35 min at 0 °C,
the reaction mixture was quenched with H2O and extracted with
EtOAc. The organic layer was dried over anhydrous Na2SO4,
filtered, and evaporated. Column chromatography (SiO2, 2.5 × 3
cm, 30% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)oxazol-
2-yl]-hept-6-yne (3b; 340 mg, 1.36 mmol, 77%) as a tan solid: 1H
NMR (CDCl3, 500 MHz) δ 8.68-8.66 (m, 1H), 7.89-7.86 (m,
2H), 7.82 (td, 1H, J ) 7.6, 1.8 Hz), 7.34-7.31 (m, 1H), 3.15 (t,
2H, J ) 7.3 Hz), 2.27 (td, 2H, J ) 7.2, 2.7 Hz), 1.96 (t, 2H, J )
2.7 Hz), 1.94-1.88 (m, 2H), 1.68-1.62 (m, 2H); 13C NMR (CDCl3,