Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies.

Abstract 4-Cyclohexylbutyl- N -[( S )-2-oxoazetidin-3-yl]carbamate ( 3b ) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure–activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b , and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak , a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b . This favourable profile, along with the structural diversity of the carbamic acid chain of 3b , identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.