Synthesis, biological evaluation, and 3D QSAR study of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters as N -acylethanolamine acid amidase (NAAA) inhibitors

Research output: Contribution to journalArticlepeer-review

Authors

  • Stefano Ponzano
  • Anna Berteotti
  • Rita Petracca
  • Romina Vitale
  • Luisa Mengatto
  • Tiziano Bandiera
  • Andrea Cavalli
  • Daniele Piomelli
  • Fabio Bertozzi

Colleges, School and Institutes

External organisations

  • Istituto Italiano di Tecnologia
  • Università di Bologna
  • University of California, Irvine

Abstract

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.

Details

Original languageEnglish
Pages (from-to)10101-10111
Number of pages11
JournalJournal of Medicinal Chemistry
Volume57
Issue number23
Early online date7 Nov 2014
Publication statusPublished - 11 Dec 2014

ASJC Scopus subject areas