Stereochemistry of phenylpiracetam and its methyl derivative: Improvement of the pharmacological profile

Since the discovery of piracetam its structural analogs based on the pyrrolidin-2-one pharmacophore have aroused great interest as a source of effective pharmacological central nervous system agents capable to facilitate memory processes and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age, and age-related pathologies. The present review summarizes the data published during the last decade concerning the design, synthesis, and biological activity exploration of enantiomerically pure (4R)-2-oxo-4-phenylpyrrolidine-1-carboxamide ((R)-phenylpiracetam) and (4R,5S)-5-methyl-2-oxo-4-phenylpyrrolidine-1-carboxamide (E1R) and providing evidence for the direct relationship between the configuration of the stereocenters and biological properties of the respective enantiomers. The methodological approaches leading to the preparation of the single stereoisomers of molecules with one or two chiral centers are reviewed. The results of comparative pharmacological testing of individual enantiomers provides the evidence of their pharmacological advantages, justifying the choice of the most effective stereoisomer and the necessity for drug substance purification from the less active one(s).