Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity

Abstract

(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.

Diverse mechanisms of antiepileptic drugs in the development pipeline

“…Seleteracetam and brivaracetam are derivatives of levetiracetam that are substituted at the 4-position on the 2-pyrrolidinone ring (Kenda et al, 2004). Both have 10-fold greater affinity for SV2A than does levetiracetam, but brivaracetam may also have modest sodium-channel blocking activity.…”

A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

“…brivaracetam (BRV) is an analog of LEV, rationally designed to have a higher affinity and selectivity for SV2A, a protein involved in synaptic vesicle exocytosis and neurotransmitter release [5,6]. Brivaracetam chemically is a 4-npropyl analog of levetiracetam and a racetam derivative with anticonvulsant properties [7,8]. Literature survey pharmacokinetics and metabolism of 14C-brivaracetam, metabolism studies of brivaracetam and gemfibrozil, clinical trials of adjunctive brivaracetam for refractory partial-onset seizures, identification of drug metabolites in human plasma or serum integrating metabolite prediction, by LC-HRMS methods are reported for the drug [9][10][11][12][13].…”

Drug Discovery in Epilepsy: A Synthetic Review

“…Brivaracetam (UCB 34714), the n-propyl derivate of LEV, possesses a ten-fold higher binding affinity for SV2A compared to LEV and it shows as a very promising new AED but still is under development (Malawka & Kulig, 2008). The main chemical disconnection of both LEV and brivaracetam occurs at the C-Npyrrolidinone bond, which can be accomplished by the alkylation of N-pyrrolidinone or Nalkyl intermediate with an activated butyric acid derivative (method A) as well as by the construction of the pyrrolidinone ring from (s)-aminobutyramide or the methyl ester of (s)-aminobutyric acid as nitrogen source (method B and C, respectively) (Kenda et al, 2004). Enantiomerically pure (s)-aminobutyric acid derivatives are readily available from Lmethionine and easier to obtain than the required butyric acid derivate in method A.…”