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.
Highlights
Identifying novel molecular targets for the treatment of pain and inflammation is of pivotal therapeutic importance and remains a major challenge for researchers in industry and academia [1]
Nacylethanolamine acid amidase (NAAA) belongs to the N-terminal nucleophile (Ntn) family of enzymes and catalyses the deactivating cleavage of saturated and monounsaturated fatty acid ethanolamides (FAEs) into the corresponding free fatty acids and ethanolamine [3,4,9,10], interrupting their peroxisome proliferator-activated receptorea (PPARa) mediated actions
In a previous study on NAAA inhibitors we reported that aamino-b-lactam (3-aminoazetidin-2-one) amide derivatives display a set of pharmacological and physicochemical properties that render them suitable for systemic administration, overcoming the limited hydrolytic and plasma stability of a-amino-b-lactonebased NAAA inhibitors, such as ARN077 (1, Fig. 1) [42]
Summary
Identifying novel molecular targets for the treatment of pain and inflammation is of pivotal therapeutic importance and remains a major challenge for researchers in industry and academia [1]. To overcome the limited stability of this class of inhibitors, we investigated compounds in which an a-amino-blactam (3-aminoazetidin-2-one) group replaces the b-lactone ring These compounds retain key structural features of the b-lactone series, and showed good human-NAAA (h-NAAA) inhibitory activity and favourable physicochemical properties for systemic administration [42]. The replacement of the exocyclic amide functionality with a carbamic acid ester, as in derivative 3a (Fig. 1) was beneficial for NAAA inhibitory activity (IC50 1⁄4 0.122 mM) [42,43] This prompted us to investigate further the structural and stereochemical features of this new series of derivatives, leading after a modification on the carbamic acid side chain of 3a to the discovery of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (ARN726, 3b, Fig. 1), as a novel and potent NAAA inhibitor [8]. We outline the selectivity, stability, and solubility of the best among these novel NAAA inhibitors, which might aid further experimental investigations of the roles of NAAA
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