Novel routes to either racemic or enantiopure α-amino-(4-hydroxy-pyrrolidin-3-yl)acetic acid derivatives and biological evaluation of a new promising pharmacological scaffold

• Published in: European journal of medicinal chemistry 2015-06, Vol.98, p.237-249
• Main Authors: Cecioni, Samy, Aouadi, Kaïss, Guiard, Julie, Parrot, Sandrine, Strazielle, Nathalie, Blondel, Sandrine, Ghersi-Egea, Jean-François, Chapelle, Christian, Denoroy, Luc, Praly, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Acetates - chemistry; Animals; Blood brain barrier; Chiral nitrone; CNS receptors; Cycloaddition; Drug Evaluation, Preclinical; Isoxazolidine; Male; Models, Molecular; Neuroactive analogs; Pyrrolidine; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rats; Rats, Wistar; Stereoisomerism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.05.017

Cycloaddition between (+) or (−)-menthone-derived nitrones and N-benzyl-3-pyrroline afforded enantiopure spiro-fused heterocycles. The reaction occurred enantio- and diastereo-selectively on the less hindered side of the nitrone, the 3-pyrroline N-benzyl group being oriented outwards, thus controlling the configurations of three simultaneously created chiral centers. From either (+) or (−)-menthone, both enantiomeric cycloadducts were synthesized in excellent yield. Removing the chiral auxiliary and the N-benzyl group delivered a series of enantiopure 4-hydroxy-3-glycinyl-pyrrolidine derivatives in 3–5 steps and 36 to 81 overall yields. Using two other achiral nitrones, shorter routes to racemic analogues were developed. Two of the synthesized compounds markedly lowered extracellular glutamate level and modestly interacted with cannabinoid type-1 receptors. As these two neuroactive compounds were devoid of in vitro toxicity and did not cross the blood brain interface, they might represent potential pharmacological agents to target peripheral organs. [Display omitted] •Novel α-amino-(4-hydroxy-pyrrolidin-3-yl)acetic acid derivatives are reported.•Synthesis of racemic or enantiopure derivatives requires from 3 to 5 steps.•Biological evaluation reveals clear-cut glutamate lowering properties for two compounds.•Biological evaluation reveals modest cannabinoid properties for two compounds.