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, 2 (2), 91-96

Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor


Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor

Douglas S Johnson et al. ACS Med Chem Lett.


Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k(inact)/K(i) and IC(50) values of 40300 M(-1) s(-1) and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials.


Figure 1
Figure 1
Selectivity profiling of PF-04457845 (23) and URB597 (2) by competitive ABPP. Gel images of proteomes labeled with FP-rhodamine in the presence or absence of FAAH inhibitors (lane 1, DMSO; lane 2, 2 at 100 μM; lane 3, 2 at 10 μM; lane 4, 23 at 100 μM; lane 5, 23 at 10 μM; and lane 6, DMSO). Gel profiles of FP-rhodamine-labeled mouse and human (A) liver soluble serine hydrolases and (B) brain membrane serine hydrolases in the presence or absence of 23 and 2. The band on the gel corresponding to the FAAH enzyme is highlighted by the black arrow. Note that 2, but not 23, blocks FP-rhodamine labeling of several liver serine hydrolases (red arrows and bracket). For both A and B, fluorescent gel images are shown in grayscale.
Scheme 1
Scheme 1. Synthesis of PF-04457845 (23)
Reagents and conditions: (a) K2CO3, DMF, 90−95 °C, 16 h, quant. (b) SOCl2, CH2Cl2, room temperature, 2 h, quant. (c) P(OEt)3, 130 °C, 16 h, 80%. (d) N-Boc-piperidin-4-one, t-BuOK, THF, 69%. (e) HCl, dioxane, 84%. (f) i-Pr2NEt, CH3CN, RT, 16 h, 86%.
Figure 2
Figure 2
Antihyperalgesic effects of PF-04457845 (23) in the CFA model of inflammatory pain in rats. Compound 23, at 0.1 to 10 mg/kg (po), produced a reduction of mechanical allodynia (hyperalgesia) in rats (black bars). The effect of the nonsteroidal anti-inflammatory drug naproxen (10 mg/kg, po, hatched bar) is shown for comparison. The antihyperalgesic responses were determined at 4 h following drug treatment and were significantly different for 23 (0.1−10 mg/kg, po) and naproxen (10 mg/kg, po) as compared to vehicle-treated groups (p < 0.05), n = 8 rats per group.

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