Another essential challenge for epilepsy research is to develop therapeutics that would not only symptomatically suppress seizures, RG7420 mw but would also inhibit or reverse progression of the EVP4593 purchase sickness (the so-called “disease modifying” drugs; Perucca et al., 2007; Bialer and White, 2010). Presently, the compounds at different stages of development belong to various chemical classes and display diverse, often unknown mechanisms of action

(Bialer et al., 2013). Most of these agents have been identified initially through in vivo screening in animal models of epilepsy rather than by a mechanistic approach. Although the animal models utilized for screening are associated with certain endpoints, it is generally accepted that they offer a good starting point in the early discovery of new AED candidates (Löscher and Schmidt, 1994; Malawska, 2005; Rogawski, 2006; Smith et al., 2007; Bialer and White, 2010; Banerjee and Sharma, 2012; Mishra and Ganguly, 2012). Recently, we have reported that chiral, bicyclic 2,6-diketopiperazines (2,6-DKPs) derived from

cyclic amino acids display a broad anticonvulsant activity in various animal models of epilepsy (Dawidowski et al., 2011, 2012a). Among the newly developed agents, compound ADD408003 exhibited a broad spectrum of seizure-suppressing activity. A preliminary structure–activity relationship (SAR) study of close analogs revealed that several factors are responsible for the anticonvulsant activity (Fig. 1): the (S,S) absolute configuration on the stereogenic centers, the presence of imide moiety and the benzene Dorsomorphin datasheet ring adjacent to 2,6-DKP core. Further, neither substitution of the imide nitrogen of ADD408003 with different alkyl and arylalkyl moieties nor expansion of the fused pyrrole chain markedly influenced the antiseizure activity. Fig. 1 Preliminary SAR of anticonvulsant 2,6-DKPs and proposed PR-171 in vitro structural modifications These findings led us to ask whether the related monocyclic 2,6-DKPs, derived from non-polar l-amino acids other than l-proline or l-homoproline display comparable anticonvulsant

activity. The designed compounds fulfill all requirements determined on the basis of the preliminary SAR analysis, i.e., proper stereochemistry, the presence of imide moiety and benzene ring attached to 2,6-DKP scaffold. Further, due to the absence of the fused pyrrolidine or piperidine rings, these agents are less sterically constrained, which might allow for a better fit to the putative receptor(s). Results and discussion Chemistry The target enantiopure, monocyclic 2,6-DKP derivatives 3a–e were synthesized according to the reaction sequences depicted in Scheme 1. Scheme 1 Synthesis of enantiopure 2,6-DKP derivatives 3a–e In the first step, the Ugi five-center four-component reaction (U-5C-4CR; Demharter et al.