Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors

Abstract

Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.

Keywords: FAAH inhibition; Ibuprofen amides; endocannabinoids; fatty acid amide hydrolase; induced fit docking.

Figure 1.

(a) 3D structure of the homo-dimer rat FAAH (rFAAH) model complexed with Anandamide (AEA). Monomer a and b are shown as green and orange cartoon, respectively. The membrane bilayer is indicated as dashed black line. (b) Details of the rFAAH binding cavity and channels. Key aminoacids of the binding cavity are highlighted as green sticks: Ser217:Ser241:Lys142 (catalytic triad), membrane access channel (MAC), the cytosolic port (CP) and the acyl-chain binding pocket (ACB).

Scheme 1.

Synthesis of Ibuprofen amides 3–16. (i) EDC, OH-Bt, MeCN, r.t. 24 h.

Scheme 3.

Synthesis of Ibuprofen amides 30–34. (i) EDC, OH-Bt, MeCN, r.t. 12 h, (ii) TFA, CH2Cl2, r.t., 24 h.; (iii) NaBHAc3, NaHCO3, ArCHO, r.t., 24 h.

Figure 2.

The lowest emodel binding modes of (S)-benzylamides : (a) 3, (b) 11 and 15. Key interacting residues of FAAH are displayed as green, cyan and orange lines relatively to benzylamides 3, 11, and 15 that are represented as green, cyan and orange sticks, respectively. Hydrogen bond interactions detected by Maestro 11.1 are shown as dashed black lines.

Scheme 2.

Synthesis of Ibuprofen amides 18–27. (i) EDC, OH-Bt, MeCN, r.t. 12 h.

Figure 3.

Superposition between the lowest emodel binding mode of (S)-piperazinoarylamides: (a) 19, 20 and 21 depicted as yellow, purple and dark-green sticks, respectively; (b) 25 and 26 dysplayed as brown and violet sticks, respectively. rFAAH key residues involved in ligand interactions are displayed as lines coloured relatively as the interacting ligand. Hydrogen bond interactions and T-shaped π-π stacking interaction detected by Maestro 11.1 are shown as dashed black lines. Globally, the substitution of a chorine atom to the phenyl ring (compound 19) allows an Hbond interaction with Cys269. The addition of a one more methyl group on the aromatic ring (amide 26) does not affect the binding mode of the two ligands, except for the phenyl ring itself that in the case of amide 26 is slightly oriented toward the Phe381 residue engaging one T-shape π-π stacking interaction.