Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABAA Receptor Negative Allosteric Modulators.

The discovery and characterization of novel naphthyridine derivatives with selective α5-GABAAR negative allosteric modulator (NAM) activity are disclosed. Utilizing a scaffold-hopping strategy, fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among these, 1,6-naphthyridinones were identified as potent and selective α5-GABAAR NAMs with metabolic stability, cardiac safety, and beneficial intellectual property (IP) issues. Relocation of the oxo acceptor function and subsequent modulation of the physicochemical properties resulted in novel 1,6-naphthyridines with improved profile, combining good potency, selectivity, ADME, and safety properties. Besides this, compound 20, having the most balanced profile, provided in vivo proof of concept (POC) for the new scaffold in two animal models of cognitive impairment associated with schizophrenia (CIAS).

In vitro dissolution-permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using µFlux™.

Since it is a well-known fact that among the newly discovered active pharmaceutical ingredients the number of poorly water soluble candidates is continually increasing, dissolution enhancement of poorly water soluble drugs has become one of the central challenges of pharmaceutical studies. So far the preclinical studies have been mainly focused on formulation methods to enhance the dissolution of active compounds, in many cases disregarding the fact that the formulation matrix not only affects dissolution but also has an effect on the transport through biological membranes, changing permeation of the drug molecules. The aim of this study was to test an electrospun cyclodextrin-based formulation of aripiprazole with the novel µFlux apparatus, which monitors permeation together with dissolution, and by this means better in vitro-in vivo correlation is achieved. It was evinced that a cyclodextrin-based electrospun formulation of aripiprazole has the potential to ensure fast drug delivery through the oral mucosa owing to the ultrafast dissolution of the drug from the formulation and the enhanced flux across membranes as shown by the result of the novel in vitro dissolution and permeation test.