(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.

No abstract

The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-D-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid mu- and delta-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.

No abstract

Capitalizing on the proven clinical efficacy of levetiracetam as an antiepileptic drug, a drug discovery program lead to the identification of a new generation of SV2A ligands with equal or better tolerability profiles than levetiracetam, and improved potency toward seizure suppression in animal models.