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Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain

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Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain

Harry R Chobanian et al. ACS Med Chem Lett.

Abstract

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

Keywords: CNS; FAAH; Fatty acid amide hydrolase; MK-4409; enzyme; inflammatory pain; inhibitor; neuropathic pain; oxazole; pyrazole.

Figures

Figure 1
Figure 1
Known covalent and noncovalent modifying FAAH inhibitors.
Figure 2
Figure 2
Key FAAH inhibitor pyrazole/oxazole compounds.
Scheme 1
Scheme 1. Synthesis of Analogues 1113
Reagents and conditions: (a) Hunig’s base, THF, rt; then DMF-DMA, 100 °C, 59% (18a), 86% (18b), 78% (18c); (b) hydrazine, EtOH, 120 °C, 89% (19a), 86% (19b), 83% (19c); (c) for 11, iodobenzene, K2CO3, K3PO4, CuI, trans-N,N′-dimethyl-1,2-cyclohexane diamine, CH3CN, 77%, for 12, 4-F iodobenzene, K2CO3, K3PO4, CuI, trans-N,N′-dimethyl-1,2-cyclohexane diamine, CH3CN, 59%; (d) 3-iodopyridine, K2CO3, CuI, d,l-proline, DMSO, 80 °C, 96%; (e) HO-NH2 (aq), EtOH, 80 °C, quant; (f) triethylorthoformate, TsOH, 80 °C, 94%.
Scheme 2
Scheme 2. Synthesis of 16 and 17
Reagents and conditions: (a) bis-pinacolatodiboron, Pd(dppf)Cl2·CH2Cl2, dppf, KOAc, dioxane, 100 °C; (b) R2X, Pd(PPh3)Cl2, 2.0 M Na2CO3, dioxane, 90 °C, 67% over 2 steps; (c) NBS, TFA, DCM, rt, 60–66%; (d) R3SH, K2CO3, NMP, 120 °C, 69–85%.
Figure 3
Figure 3
SNL efficacy of compound 17 (MK-4409).
Figure 4
Figure 4
SNL efficacy of compound 17 (MK-4409) at 50% reversal plotted against rota-rod impairment at 20% (adverse effect) compared to current standards of care or positive controls.
Figure 5
Figure 5
Chronic dosing of compound 17 versus WIN 55,212-2 in CFA pain model along with plasma exposure.

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