Synthesis, biological evaluation, and 3D QSAR study of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters as N-acylethanolamine acid amidase (NAAA) inhibitors.
N-(2-Oxo-3-oxetanyl)carbamic acid esters have recently been reported to be noncompetitive inhibitors of the N-acylethanolamine acid amidase (NAAA) potentially useful for the treatment of pain and inflammation. In the present study, we further explored the structure-activity relationships of the carbamic acid ester side chain of 2-methyl-4-oxo-3-oxetanylcarbamic acid ester derivatives. Additional favorable features in the design of potent NAAA inhibitors have been found together with the identification of a single digit nanomolar inhibitor. In addition, we devised a 3D QSAR using the atomic property field method. The model turned out to be able to account for the structural variability and was prospectively validated by designing, synthesizing, and testing novel inhibitors. The fairly good agreement between predictions and experimental potency values points to this 3D QSAR model as the first example of quantitative structure-activity relationships in the field of NAAA inhibitors.
Drug Discovery and Development, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
Stefano
S
Ponzano
Anna
A
Berteotti
Rita
R
Petracca
Romina
R
Vitale
Luisa
L
Mengatto
Tiziano
T
Bandiera
Andrea
A
Cavalli
Daniele
D
Piomelli
Fabio
F
Bertozzi
Giovanni
G
Bottegoni
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis*; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
D002219:Carbamates; D004791:Enzyme Inhibitors; D004952:Esters; D000581:Amidohydrolases; C575348:N-acylethanolamine-hydrolyzing acid amidase, rat; C523108:NAAA protein, human; C070766:carbamic acid