Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions

Pioneering first‐in‐class FAAH‐HDAC inhibitors as potential multitarget neuroprotective agents

“…T A B L E 1 Inhibitory activity of the novel compounds 4a-j on human (h) FAAH and human (h) HDAC6 enzymes. [15] -2 -10.1 ± 0.6 [17] -3 --36.0 ± 2.9 [30] Abbreviations: FAAH, fatty acid amide hydrolase; HDAC, histone deacetylase. In Scheme 3, the synthesis of phenols 23a-d is displayed.…”

“…[ 14 ] To improve the physicochemical properties of this type of derivative, we subsequently developed a novel series of derivatives characterized by more polar and protonatable lateral chains, as exemplified by compound 2 ( h FAAH IC 50 = 10.1 ± 0.6 nM, Figure 1), which showed a marked anti‐inflammatory and neuroprotective profile in hippocampal rat explants. [ 17 ]…”

“…[11][12][13] Recently, we disclosed wide libraries of carbamate-based FAAH inhibitors (FAAHis). [14][15][16][17] These derivatives share a common pharmacophore that combines an electrophilic center undergoing nucleophilic attack by the catalytic Ser241, a suitably decorated biaryl leaving group, and a lateral chain that can exhibit various levels of lipophilicity to mimic the AEA apolar tail. Among them, the 1-phenylpyrrolic compound 1 (mFAAH IC 50 = 0.60 nM, hFAAH IC 50 = 3.72 nM, Figure 1) emerged as a potent and selective FAAHi endowed with in vivo efficacy in a murine model of epilepsy.…”

“…[14] To improve the physicochemical properties of this type of derivative, we subsequently developed a novel series of derivatives characterized by more polar and protonatable lateral chains, as exemplified by compound 2 (hFAAH IC 50 = 10.1 ± 0.6 nM, Figure 1), which showed a marked anti-inflammatory and neuroprotective profile in hippocampal rat explants. [17] Epigenetic regulation plays a pivotal role in virtually every biological process. The alteration of HDAC levels is associated with the onset and development of various diseases, including cancer, genetic disorders such as Rett syndrome, Charcot-Marie-Tooth disease and retinitis pigmentosa, as well as idiopathic pulmonary fibrosis, and several neurodegenerative diseases.…”

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization

“…Modulation of the ECS throughout interference with FAAH and MAGL activities is part of our scientific interest. We have recently developed selective or dual-acting FAAH and MAGL inhibitors as pharmacological tools for exploring different potential therapeutic applications. − An example is the potent and selective MAGL inhibitor (±)- 4 (Figure ), in which the Y shape of the diphenylmethane derivatives 1 – 3 was mimicked and challenged by exploiting the trans -3,4-diaryl-substituted β-lactam structural motif. The azetidin-2-one could support the aromatic rings (namely the key pharmacophoric elements), allowing their correct reciprocal orientation and distance for interaction in their enzymatic binding site.…”