Jean-Philippe Starck

Discovery of Indolone Acetamides as Novel SV2A Ligands with Improved Potency Toward Seizure Suppression

A major goal in epilepsy research is to develop new antiepileptic drugs (AEDs) that combine improved seizure control with enhanced tolerability while avoiding drug–drug interactions. Although the prognosis for seizure control is acceptable in up to 70 % of patients, approximately 30 % suffer from intractable pharmaco-resistant epilepsy. 3] Furthermore, the clinical use of most older AEDs is hampered by their limited tolerability; this most commonly consists of CNS-related adverse effects, idiosyncratic reactions such as skin rashes, and the potential for unfavorable drug–drug interactions. It was previously reported that the AED levetiracetam (2 ; Keppra ) has a unique brainspecific binding site. This site was recently identified as the synaptic vesicle protein 2A (SV2A). A strong correlation between the affinity of levetiracetam analogues for SV2A and their anti-seizure potency in the audiogenic mouse model of epilepsy has been reported. This suggests that levetiracetam’s interaction with SV2A has a major functional role in its anticonvulsant mechanism of action. SV2, a protein specific to synaptic vesicles, is a 12-transmembrane region glycoprotein present in all neural cells, and it is present in three isoforms: SV2A, SV2B, and SV2C. SV2A is the most widely distributed isoform and is ubiquitous in the CNS, but is also present in endocrine cells. Although the exact molecular role of SV2A is still unknown, it is believed to play a role in the exocytosis of neurotransmitters and to act as a modulator of vesicle fusion. Given the proven clinical efficacy of levetiracetam as an AED, its unique mechanism of action, and its excellent tolerability, we decided to initiate a drug discovery program focused on SV2A as a novel molecular target. The aim was to identify a new generation of SV2A ligands with an equal or better tolerability profile than 2 and an improved potency toward seizure suppression in animal models. At the outset of our work in the SV2A field, we systematically investigated the various positions of the pyrrolidone acetamide scaffold of 2. Among others, we discovered the importance of the carboxamide moiety on 2 and the preferred substitution position a to the carboxamide. This research lead to the identification of two compounds currently in clinical development: brivaracetam (3) and seletracetam (4), both of which are more potent than 2 in vitro toward SV2A and in vivo as anticonvulsant agents in audiogenic seizure-prone mice. (Figure 1)

Alkyne–quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD

SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.