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.

Progress in the development of β-lactams as N-Acylethanolamine Acid Amidase (NAAA) inhibitors: Synthesis and SAR study of new, potent N-O-substituted derivatives

“…After intravenous and oral administration in rat, compound 2 exhibited a good oral bioavailability (F ¼ 67%), supporting the use of such class of compounds for systemic administration [20]. Additionally, as demonstrated by a recently published SAR study, the functionalization of the exocyclic amino group of the b-lactam scaffold as a carbamate afforded compounds with potent NAAA inhibitory activity [21]. Notably, compound 3 (ARN0726, Fig.…”

“…A slight modification of the reported synthetic pathway to unprotected serine-derived b-lactams [21] provided an efficient procedure to easily prepare the new N-substituted analogues. Basedcatalyzed nucleophilic substitutions using 3 (ARN0726) and the corresponding methyl iodide, acetyl chloride and methylchloroformate afforded compounds 4, 5, and 6, respectively, in moderate yield (Scheme 1).…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…For instance, the covalent adducts of NAAA-125 were detected by mass spectrometry in mice lungs 139 Notably, compound 125 was disclosed as the first β- More recently, the optimization of the β-lactam moiety or the side chain of carbamate-based β-lactams was carried out. 140 The investigation of structure activity-relationships disclosed that a linear and lipophilic side chain is favorable for NAAA inhibitory capacity, and (S)-configuration is preferred rather than its (R)-isomer. Specifically, compounds 126, 127 and 128 ( Figure 43) possessed encouraging 39 inhibitory potency towards NAAA (IC50 = 12 nM, 7 nM, and 22 nM, respectively, evaluated by UPLC/MS-based assay).…”

Synthesis, Separation and Absolute Configuration Determination by ECD Spectroscopy and TDDFT Calculations of 3‐Amino‐β‐lactams and Derived Guanidines

“…Since the discovery of penicillin in 1929, natural and synthetic -lactams have been among the most used and most versatile antibiotics. [6] Moreover, the -lactam derivative ezetimibe is the only cholesterol absorption inhibitor on the market today. [1] However, in recent decades, several new classes of pharmaceutically interesting -lactam derivatives have emerged.…”

“…[6] We have, on the other hand, recently developed new ezetimibe analogues from 3amino--lactam by introducing side-chain functional groups applying N-alkylation [8] or N-acylation reactions (Scheme 1). [6] We have, on the other hand, recently developed new ezetimibe analogues from 3amino--lactam by introducing side-chain functional groups applying N-alkylation [8] or N-acylation reactions (Scheme 1).…”