Table 1.
Potencies of leading FAAH and MAGL inhibitors with sub-hundred nanomolar potency.
| Name | FAAH Inhibition (IC50, nM) | Reversibility | MAGL Inhibition (IC50, nM) |
Reversibility | Inhibition of other Enzymes or Receptors (IC50, nM) | In Vivo Efficacy on Brain |
|---|---|---|---|---|---|---|
| AM3506 [123] | 48 (h) [123] 2.8 ± 0.3 (r) [112] 5.1 ± 0.5 (h) [112] |
Irreversible [112] | 11,000 (h) [123] 383.1 ± 42.3 (h) [112] |
N.A. | N.A. | Yes [123] |
| AM374 (hexadecylsulfonyl fluoride) [124] | 13 (r) [124] 10.2 ± 0.1 (r) [125] |
Irreversible [124] | 6,200 ± 100 (r) [126] 241 ± 17 (r) [127] |
N.A. | 520 (462–586) (r CB1 agonist binding) [124] | N.A. |
| AM6701 [118] | 1.2 ± 0.13 (h) [128] | N.A. | 1.7 (r) [118] 0.9 (h) [118] 20 (monkey) [115] 1.2 ± 0.35 (h) [128] |
Slowly reversible [129] | 7.2 ± 2.5 (h NAAA) [130] 7.7 ± 0.2 (h NAAA) [130] |
N.A. |
| CAY10435 [131] | 0.81 (0.56–1.1) (m) [132] 17 (h) [133] |
Reversible [133] | N.A. | N.A. | 50,000 (21,000–120,000) (m KIAA1363) [132] 83 (69–100) (m TGH) [132] |
Yes [134] |
| CAY10499 [135] | 76 (h) [135] 86 (70–110) (r) [136] 1,300 (r) [114] |
Irreversible [135] | 500 ± 30 (h) [135] 92 (82–100) (h) [136] 480 (h) [114] 144 ± 3 (h) [137] |
Irreversible [137, 138] | 90 (h HSL) [136] | N.A. |
| IDFP [139] | 3 ± 2 (m) [139] | N.A. | 0.8 ± 0.2 (m) [139] 0.107 (r) [140] 0.219 (m) [140] 1.5 (h) [140] |
N.A. | 6,300 ± 2,300 (m AChE) [139] 2 ± 1 (m CB1 agonist binding) [141] |
Yes [139, 141] |
| JJKK-048 [140] | 2,400 (r) [140] 4,800 (h) [140] |
N.A. | 0.214 (r) [140] 0.275 (m) [140] 0.363 (h) [140] |
N.A. | 229 (h ABHD6) [140] | N.A. |
| JNJ-1661010 (Takeda-25) [142, 143] | 10 (r FAAH) [142] 12 (h FAAH) [142] 15–388 (h FAAH) [142] 34 ± 6.5 (r) [143] 33 ± 2.1 (h) [143] |
Partially reversible (80% recovery) [142] | No inhibition (r) [142] | N.A. | 5,700 (h FAAH-2) [142] No inhibition (r COX-1) [142] No inhibition (r COX-2) [142] No inhibition (r NAAA) [142] |
Yes [142] |
| JNJ-40355003 (JNJ-5003) [144] | 1.4 ± 0.41 (h) [144] 33 ± 8.7 (r) [144] |
N.A. | N.A. | N.A. | >10,000 (h FAAH-2) [144] | Yes [144] |
| JW618 [145] | >50,000 (m) [145] >50,000 (r) [145] >50,000 (h) [145] |
N.A. | 123 (91–160) (m) [145] 385 (329–451) (r) [145] 6.9 (4.4–11) (h) [145] |
N.A. | 38 (29–50) (m ABHD6) [145] 13 (8.9–18) (r ABHD6) [145] |
N.A. |
| JW651 [146] | >50,000 (m) [146] | N.A. | 4.5 (m) [146] 38 (23–64) (m) [146] |
N.A. | 10,380 (4,612–23,400) (m ABHD6) [146] | Yes [146] |
| JZL184 [147] |
4,000 (m) [147] 4,690 (m) [148] 3,570 (2,540–5,020) (r) [145] >50,000 (h) [145] 36,308 (h) [149] |
N.A. | 8 (m) [147] 6 (m) [147] 2 (m) [85] 25 (r) [85] 2 (h) [85] 10 (m) [148] 262 (188–363) (r) [145] 3.9 (1.8–8.1) (h) [145] 37 (h) [149] 2,700 (r) [140] 95 (m) [140] |
Irreversible [85, 138] | 3,270 (m ABHD6) [148] 2,940 (1,441–6,010) (r ABHD6) [145] 5 (u ES1) [85] 5 (u TGH2) [85] >100,000 (u HSL) [85] |
Yes [145, 147] |
| Name | FAAH Inhibition (IC50, nM) | Reversibility | MAGL Inhibition (IC50, nM) |
Reversibility | Inhibition of other Enzymes or Receptors (IC50, nM) | In Vivo Efficacy on Brain |
| JZL195 [150] | 13 (m) [150] 12 (r) [150] 110 (h) [150] |
N.A. | 19 (m) [150] 100 (r) [150] 5 (h) [150] 3,700 (r) [140] 3,300 (m) [140] |
N.A. | 50 (m ABHD6) [150] >5,000 (m NTE) [150] 50 (r ABHD6) [150] >5,000 (r NTE) [150] >5,000 (h NTE) [150] >20,000 (h CB1 agonist binding) [150] >20,000 (h CB2 agonist binding) [150] |
Yes [150] |
| JZP-327A [133] | 11 (h) [133] | Slowly reversible [133] | 16% inhibition at 10 μM (h) [133] | N.A. | No inhibition at 10 μM (bovine COX-1) [133] 20% inhibition at 10 μM (h COX-2) [133] |
N.A. |
| KML29 [145] | >50,000 (m) [145] >50,000 (r) [145] >50,000 (h) [145] |
N.A. | 2.5 (m) [145] 15 (11–21) (m) [145] 43 (36–52) (r) [145] 5.9 (4.0–9.9) (h) [145] 0.14 (h) [145] 2.5 (r) [140] 0.851 (m) [140] 3.6 (h) [140] |
N.A. | 4,870 (4,120–5,760) (m ABHD6) [145] 1,600 (1,260–2,040) (r ABHD6) [145] |
Yes [145, 151] |
| LY2183240 [152] | 2.1 (r) [115] 12.4 (8.3–18.6) (m) [153] 14.0 ± 0.662 (r) [154] 37.3 ± 5.4 (h) [155] 5 (r) [114] |
Irreversible [153] | 8,100 (monkey) [115] 5.3 (3.9–7.3) (u) [153] 54.4 ± 5.2 (h) [155] 290 (h) [114] |
N.A. | 0.27 ± 0.029 (AEA uptake in RBL-2H3 cells) [152] 0.09 (0.07–0.10) (u ABHD6) [153] 8.2 (6.1–11) (u KIAA1363) [153] |
Yes [152, 153] |
| MAFP [156, 157] | 2.5 (m) [157] 1–3 (m, r) [156] 6 (porcine) [158] 0.10 ± 0.02 (m) [159] 0.33 ± 0.07 (h) [155] |
Irreversible [156, 157] | 2–3 (porcine) [158] 800 ± 50 (r) [126] 2.2 ± 0.3 (r) [127] 76 ±4 (h) [135] 26.3 ± 9.95 (h) [155] 62–160 (h) [160] 1.0 (r) [140] 1.8 (m) [140] |
Irreversible [138, 155] | 20 (r CB1 agonist binding) [157] 0.60 ± 0.10 (m NTE) [113] 124 ± 17 (m AChE) [159] |
Yes [134] |
| MJN110 [161] | >50,000 (m) [161] >50,000 (h) [161] >100,000 (m) [146] |
N.A. | 2.1 (m) [161] 9.1 (h) [161] 0.43 (h) [161] 9.5 (5.7–15.8) (m) [146] |
N.A. | 260 (174–394) (m ABHD6) [146] | Yes [161] |
| ML30 [149] | 562 (h) [149] | N.A. | 0.54 (h) [149] 4.4 (r) [140] 1.9 (m) [140] 1.5 (h) [140] |
Irreversible [149] | N.A. | N.A. |
| N-arachidonoyl maleimide [162] | >10,000 (r) [114] 2,180 ± 620 (h) [155] |
N.A. | 140 (r) [162] 10,500 ± 3,800 (h) [135] 2,800 (h) [118] 1,120 ± 140 (h) [155] 46 ± 7 (r) [163] No inhibition at 10 μM (h) [114] 148 (r) [140] 324 (m) [140] |
Irreversible [138, 164] | N.A. | Yes [10] |
| Name | FAAH Inhibition (IC50, nM) |
Reversibility | MAGL Inhibition (IC50, nM) |
Reversibility | Inhibition of other Enzymes or Receptors (IC50, nM) | In Vivo Efficacy on Brain |
| OL-135 [165] | 206 (126–336) (h FAAH-1) [41] 208–297 (h) [166] 2.1 (1.5–3.0) (m) [120] 1,100 (h FAAH-HEK whole cell assay) [167] |
Reversible [165, 166] | >100,000 (m) [120] | N.A. | 13.4 (11.3–15.9) (h FAAH-2) [41] 4 (h FAAH-2) [142] 620 (490–780) (m TGH) [120] >100,000 (m AAD) [120] >100,000 (m CE-1) [120] >100,000 (m LPL) [120] >100,000 (m KIAA1363) [120] 22% inhibition at 10 μM (r CB1) [120] 30% inhibition at 10 μM (h CB2) [120] |
Yes [120] |
| OL-92 [165] | 0.28 (0.15–0.52) (m) [120] | Reversible [120] | >100,000 (m) [120] | N.A. | >100,000 (m TGH) [120] >100,000 (m AAD) [120] >100,000 (m CE-1) [120] >100,000 (m LPL) [120] 17000 (9500–28000) (m KIAA1363) [120] |
No, not active in vivo [120] |
| PF-04457845 (PF-7845) [168] | 7.2–50.4 (h) [169] 7.4–43.1 (r) [169] 2.5 (m) [170] 1.0 (h) [170] |
Irreversible [168] | No inhibition at 10 μM (m) [170] No inhibition at 10 μM (h) [170] |
N.A. | 30,000 (h CYP1A2) [168] 9,800 (h CYP2C9) [168] 12600 (h CYP2C19) [168] 14,500 (h CYP2D6) [168] 30,000 (h CYP3A4) [168] No inhibition at 10 μM (m ABHD6) [170] |
Yes [169, 170] |
| PF-3845 [171] | 18 (14–23) (h FAAH-1) [171] | Irreversible [171] | N.A. | N.A. | >10,000 (h FAAH-2) [171] | Yes [86, 171] |
| PF-750 [166] | 16.2–595 (h) [166] 320 (h) [133] |
Irreversible [166] | N.A. | N.A. | No inhibition at 50 μM (m liver serine hydrolases) [166] | Yes [166] |
| SA-57 [170] | 3.2 (m) [170] 1.9 (h) [170] |
Irreversible [170]. | 410 (m) [170] 1,400 (h) [170] |
Irreversible [170] | 850 (m ABHD6) [170] | Yes [170] |
| ST4070 [172] | 9 (m) [172] | Reversible [172] | >10,000 (m) [172] | N.A. | >10,000 (m CB1 agonist binding) [172] >10,000 (m CB2 agonist binding) [172] >10,000 (m TRPV1) [172] 100 (h AMT) [172] >10,000 (m NAPE-PLD) [172] >10,000 (m DAGL) [172] |
Yes [173] |
| URB597 (KDS-4103) [7] | 3.8 (2.9–5.0) (r) [127] 45 (31–65) (m) [174] 33.5 (h) [175] 26.3 (h) [175] 109 (h) [176] 119 (r) [176] 4.6 ± 1.6 (r) [7] 0.5 ± 0.05 (r) [7] 113 (79–170) (m) [120] 101–505 (h FAAH-1) [41] 157 ± 5.23 (r) [154] 109–986 (h) [166] 7.7 ± 1.5 (r) [177] 31 (h FAAH-HEK whole cell assay) [167] |
Irreversible [7, 142, 166] | >100,000 (m) [120] >30,000 (r) [7] |
N.A. | 196 (119–322) (m CE-6) [174] >100,000 (m ES31) [174] 5.0–26.3 (h FAAH-2) [41] 7 (h FAAH-2) [142] 192 (96–320) (m TGH) [120] >100,000 (m AAD) [120] >100,000 (m CE-1) [120] >100,000 (m LPL) [120] >100,000 (m KIAA1363) [120] >30,000 (h AMT) [7] >100,000 (r CB1 agonist binding) [7] >100,000 (u CB2 agonist binding) [7] |
Yes [153, 166, 174, 177] |
| URB880 [117] | 0.63 ± 0.04 (r) [117] | N.A. | No inhibition at 100 μM (r) [117] | N.A. | N.A. | N.A. |
| URB937 [178] | 26.8 ± 4.9 (r) [178] | Irreversible [119] | >100,000 (r) [178] | N.A. | N.A. | No, peripherally restricted effects [178] |
Abbreviations: FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; IC50, 50% inhibitory concentration; N.A., not available; h, human; r, rat; m, mouse; u, undescribed species; CB, cannabinoid receptor; NAAA, N-acylethanolamine-hydrolyzing acid amidase; HSL, hormone-sensitive lipase; AChE, acetylcholinesterase; ABHD, α/β-hydrolase domain 6; COX, cyclooxygenase; ES, esterase; TGH, triacylglycerol hydrolase; NTE, neuropathy target esterase; KIAA1363, ether-lipid metabolic enzyme; RBL, rat basophilic leukemia; HEK, human embryonic kidney; AAD, arylacetamide deacetylase; CE, carboxylesterase; LPL, lipoprotein lipase; CYP, cytochrome P450; AMT, anandamide membrane transporter The data are presented as mean, mean ± standard deviation, or mean (range).