3‐Heterocycle‐Phenyl N‐Alkylcarbamates as FAAH Inhibitors: Design, Synthesis and 3D‐QSAR Studies

Abstract

Carbamates are a well-established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta-substituted phenolic N-alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3-(oxazol-2yl)phenyl cyclohexylcarbamate (2 a), inhibited FAAH with a sub-nanomolar IC(50) value (IC(50)=0.74 nM). Additionally, we developed and validated three-dimensional quantitative structure-activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D-QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D-QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R(2) (PRED)) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.

Binding Affinity via Docking: Fact and Fiction

“…Our current solution is based on two comprehensive approaches, one to use docking tools in more efficient ways [ 53 , 70 ], and the other is to use MD simulations to validate the results of the classical docking [ 71 , 72 ]. Prior to any docking experiment, one should explore the flexibility of the target protein, based on both the existing protein structures and MD simulations.…”

Monomers for Adhesive Polymers, 14 Synthesis and Radical Polymerization of 4-[11-(Acryloyl-methyl-amino)-undecyloxy]-phthalic Acid and {10-[1,3-Bis(methacrylamido)-propoxy]-decyloxy}-phthalic Acid

“…Since a scale‐up of the synthesis, which would provide sufficient material for a testing in dental adhesive formulations, seemed rather impracticable under the present conditions, an alternative route had to be developed, employing hydrolytically more stable phthalic esters instead of the anhydride. The reaction of the easily accessible 4‐hydroxy‐phtalic acid dimethyl ester with 6 and K 2 CO 3 in DMF proceeded with a good yield (73%) within 6 d at room temperature, the final removal of the methyl ester protecting group, however, failed due to degradation of the acrylate‐double bond under the required strongly basic conditions. Whereas the synthesis of an acid‐labile tert ‐butyl ester of 6 could not successfully be accomplished, the methoxymethyl (MOM) ester ( 7 ) was accessible in up to a 64% yield via reaction of 6 with MOM‐chloride or ‐bromide and Hünig's base in dichloromethane at 0 °C, following a procedure for the synthesis of hydroxy‐benzoic acid MOM ester .…”

“…Column chromatography was performed on silica gel 60 (Roth AG, particle size: 0.04–0.063 mm). 4‐Hydroxy‐phthalic acid, 4‐hydroxy‐phthalic acid anhydride, and 4‐hydroxy‐phthalic acid dimethyl ester were synthesized according to procedures described in the literature. The synthesis of 1,3‐bis(methacrylamido)propan‐2‐ol (BMPOH) has previously been reported …”

Novel therapies for glaucoma: a patent review (2013-2019)

“…Another patent investigated the synthesis, characterization and formulations of three imidazole-based FAAH inhibitors [51], as reported in Table 3, alone or in combination with anandamide (the natural substrate of FAAH enzyme acting as both cannabinoid and vanilloid receptors agonist). Imidazole-based carboxamides were previously reported to inhibit FAAH [52]. In order to enhance water solubility, the same inventors developed urea-based FAAH inhibitors for the treatment of glaucoma [53].…”