Alfonso Pozzan

5-Aryl-4-carboxamide-1,3-oxazoles: Potent and selective GSK-3 inhibitors

5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.

Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: Novel, potent, and selective series of Vasopressin1b receptor antagonists

Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.

Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors.

The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3β inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.

Azabicyclo[3.1.0]hexane‐1‐carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior

Azabicyclo[3.1.0]hexane-1-carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior Fabio Maria Sabbatini,* Sergio Melotto, Giovanni Bernasconi, Steve M. Bromidge, Lucilla D’Adamo, Marilisa Rinaldi, Chiara Savoia, Claudia Mundi, Carla Di Francesco, Laura Zonzini, Vivian J. A. Costantini, Benedetta Perini, Enzo Valerio, Alfonso Pozzan, Elisabetta Perdon , Filippo Visentini, Mauro Corsi, and Romano Di Fabio*

Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.

2-Methyl-3-furanyl-4H-1,2,4-triazol-3-ylthioamides: A new class of selective orexin 2 antagonists

A new class of selective orexin 2 antagonist was identified among commercial products. Initial SAR was obtained using commercial derivatives only prior to starting ad hoc medicinal chemistry activities.

Stereoselective Synthesis of 3-Substituted Tetrahydropyrazinoisoquinolines via Intramolecular Cyclization of Enantiomerically Enriched Dihydro-2H-pyrazines

The preparation of 3-substituted tetrahydropyrazinoisoquinolines using the tributyltin hydride mediated intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines is reported. The compounds are obtained as single enantiomers, as the relative configuration of the new generated stereogenic center is driven by the stereochemistry of the 2-substituted carbon in the starting materials, which is in turn derived from naturally occurring amino acids.