An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH)
(2013) European Journal of Medicinal Chemistry — Vol. 60, p. 101-111 (2013)
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- Abstract
- A series of compound was prepared to clarify the reversible mechanism of β-lactamic hFAAH inhibitors on the one hand, and to modulate some of their physicochemical parameters on the other hand. In particular, two compounds (4b and 4e) were designed to display a potential good leaving group on the crucial carbonyl with a view to possibly acylating the active serine of the hFAAH catalytic triad. Reversibility studies showed that these two compounds retain the reversible mode of inhibition, suggesting a noncovalent interaction between our β-lactams and hFAAH. Finally, pharmacological evaluations of bioisosteres of the lead compound (4a, IC(50) = 5.3 nM) revealed that log P values and PSA could be optimized without altering the FAAH inhibition (IC(50) values from 3.65 nM to 70.9 nM).
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Feledziak, M., Michaux, C., Lambert, D., & Marchand-Brynaert, J. (2013). An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH). European Journal of Medicinal Chemistry, 60, 101-111. https://doi.org/10.1016/j.ejmech.2012.11.035 (Original work published 2013)