Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 µM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 µM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.

Design and synthesis of benzofused heterocyclic RXR modulators.

Benzofused heterocyclic analogs of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRalpha and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the choice of heterocycle as well as the sidechain employed.

Design and synthesis of fluorinated RXR modulators.

Fluorinated trienoic acid analogues of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRalpha and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the position of fluorination, and improvement in pharmacological profile was demonstrated in some cases.

In vitro studies of a bradykinin B1/B2 antagonist linked to a human neutrophil elastase inhibitor; a heterodimer for the treatment of inflammatory disorders.

Inflammatory disorders typically have a complex etiology and involve a multitude of inflammatory mediators, and hence, a polytherapeutic approach to these diseases would seem appropriate. In certain chronic inflammatory conditions, we believe that bradykinin (BK) and human neutrophil elastase (HNE) are cooperatively involved. We have previously synthesized compounds with inhibitory activity toward both the BK B2 receptor and HNE. The present study describes single compounds designed to incorporate HNE inhibitory activity and BK B1 and B2 antagonist activity. A proprietary HNE inhibitor (HNEI, CP-955) was directly linked via amide bond formation to a peptide-based combined BK B1/B2 antagonist (B-9430). Three compounds were made using different linking positions in the antagonist peptide. For all compounds, B1 and B2 receptor binding in human cloned receptors was at least 10-fold less than that of B-9430, whereas in the in vitro guinea pig ileum B2 receptor functional assay, the compounds had potencies equivalent to B-9430. Compound I was found to have a fourfold increase in HNEI activity compared with CP-955, whereas compounds II and III were inactive. These data clearly demonstrate that it is possible to retain BK B1/B2 receptor antagonist and HNE activity in a heterodimer.