14702-42-2Relevant academic research and scientific papers
Chiral 1,3,4-oxadiazol-2-ones as highly selective FAAH inhibitors
Patel, Jayendra Z.,Parkkari, Teija,Laitinen, Tuomo,Kaczor, Agnieszka A.,Saario, Susanna M.,Savinainen, Juha R.,Navia-Paldanius, Dina,Cipriano, Mariateresa,Lepp?nen, Jukka,Koshevoy, Igor O.,Poso, Antti,Fowler, Christopher J.,Laitinen, Jarmo T.,Nevalainen, Tapio
supporting information, p. 8484 - 8496 (2013/12/04)
In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl) -5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, 51), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 μM). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC 50 = 4.0 μM and 16% inhibition at 10 μM, respectively). The FAAH selectivity of the compound 51 over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected S-enantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.
Rate constants for 1,2-hydrogen migration in cyclohexylidene and in substituted cyclohexylidenes
Pezacki, John Paul,Couture, Philippe,Dunn, James A.,Warkentin, John,Wood, Paul D.,Lusztyk, Janusz,Ford, Francis,Platz, Matthew S.
, p. 4456 - 4464 (2007/10/03)
Laser flash photolysis (UV-LFP, 308 nm) of suitably substituted oxadiazolines leads to cyclohexylidene (14a), 4-tert-butyl-cyclohexylidene (14b), 2-trifluoromethylcyclohexylidene (14d), 8-aza-8-methyl[3.2.1]oct-3- ylidene (14e), diethylcarbene (14f), and ethyl(methyl)carbene (14h). Carbene intermediates were inferred from the products of steady state photolyses, and their pyridinium ylides were inferred from transient absorption spectra observed when pyridine was present. Yields of the pyridinium ylides 15a-h as a function of pyridine concentration gave the lifetimes (τ) for carbenes 14a-h in cyclohexane, cyclohexane-d12, and benzene solutions, at 22 °C. The intermediacy of cyclohexylidene (14a) was inferred from the observation of cyclohexene formed in both the LFP and steady state (SS) experiments. The major products from dual wavelength irradiation of the oxadiazolines (at 254 and 300 nm) were those of 1,2-migration of hydrogen (1,2-H) in the corresponding carbenes. 2-Trifluoromethylcyclohexylidene gave 3- trifluoromethylcyclohexene and 1-trifluoromethylcyclohexene in a 9.8:1 ratio. The kinetic data support the conclusion that 1,2-H in the cyclohexylidenes is accelerated, relative to 1,2-H in dimethylcarbene. A 4-tert-butyl substituent has a negligible effect on the rate constant for 1,2-H, but the CF3 group at the α-position decelerates 1,2-H by roughly 10-fold, as inferred from the distribution of products.
