Simone Braggio
GlaxoSmithKline
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Featured researches published by Simone Braggio.
Expert Opinion on Drug Metabolism & Toxicology | 2010
Kevin D. Read; Simone Braggio
Importance of the field: The incorporation of brain tissue binding routinely in CNS drug discovery screening strategies has markedly changed the way CNS drug discovery is performed and is proving to be a valuable tool in identifying new therapies for CNS diseases. For many years emphasis has been placed on the magnitude of the brain to blood ratio, the bigger the better, even though, in many cases, brain total concentration (Cbrain) has no or, at best, poor correlation with receptor occupancy/pharmacodynamic readout. Today, Cbrain values measured during in vivo experiments are corrected for the fraction unbound measured through in vitro experiments using brain tissue homogenate or brain tissue slice to obtain an estimate of the brain unbound concentration (Cu,brain), and this has been demonstrated across a range of CNS targets to give a much better correlation with receptor occupancy/pharmacodynamic readout. This apparently simple change in CNS lead optimisation strategy has de facto revolutionised the vision of the brain penetration concepts. Areas covered in this review: This review will provide an overview of the use and applications of assessing brain free fraction to determine Cu,brain. Take home message: Assessing brain free fraction to determine Cu,brain in CNS lead optimisation strategies is the surrogate of choice for rapidly assessing biophase concentration for the majority of CNS targets.
Journal of Medicinal Chemistry | 2010
Fabrizio Micheli; Paolo Cavanni; Daniele Andreotti; Roberto Arban; Roberto Benedetti; Barbara Bertani; Michela Bettati; Letizia Bettelini; Giorgio Bonanomi; Simone Braggio; Renzo Carletti; Anna Checchia; Mauro Corsi; Elettra Fazzolari; Stefano Fontana; Carla Marchioro; Emilio Merlo-Pich; Michele Negri; Beatrice Oliosi; Emiliangelo Ratti; Kevin D. Read; Maja Roščić; Ilaria Sartori; Simone Spada; Giovanna Tedesco; Luca Tarsi; Silvia Terreni; Filippo Visentini; Alessandro Zocchi; Laura Zonzini
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Bioorganic & Medicinal Chemistry Letters | 2011
Romano Di Fabio; Annalisa Pellacani; Stefania Faedo; Adelheid Roth; Laura Piccoli; Philip Gerrard; Rod A. Porter; Christopher Norbert Johnson; Kevin M. Thewlis; Daniele Donati; Luigi Piero Stasi; Simone Spada; Geoffrey Stemp; David John Nash; Clive Leslie Branch; Leanda Kindon; Mario Massagrande; Alessandro Poffe; Simone Braggio; Elisabetta Chiarparin; Carla Marchioro; Emiliangelo Ratti; Mauro Corsi
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Journal of Medicinal Chemistry | 2010
Fabrizio Micheli; Luca Arista; Giorgio Bonanomi; Frank E. Blaney; Simone Braggio; Anna Maria Capelli; Anna Checchia; Federica Damiani; Romano Di-Fabio; Stefano Fontana; Gabriella Gentile; Cristiana Griffante; Dieter Hamprecht; Carla Marchioro; Manolo Mugnaini; Jacqui Piner; Emiliangelo Ratti; Giovanna Tedesco; Luca Tarsi; Silvia Terreni; Angela Worby; Charles R. Ashby; Christian Heidbreder
The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Expert Opinion on Drug Discovery | 2010
Simone Braggio; Dino Montanari; Tino Rossi; Emiliangelo Ratti
As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the ‘optimal’ absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.
Journal of Medicinal Chemistry | 2008
Romano Di Fabio; Yves St-Denis; Fabio Maria Sabbatini; Daniele Andreotti; Roberto Arban; Giovanni Bernasconi; Simone Braggio; Frank E. Blaney; Anna Maria Capelli; Emiliano Castiglioni; Enza Di Modugno; Daniele Donati; Elettra Fazzolari; Emiliangelo Ratti; Aldo Feriani; Stefania Contini; Gabriella Gentile; Damiano Ghirlanda; Stefano Provera; Carla Marchioro; Karen Roberts; Anna Mingardi; Mario Mattioli; Arnaldo Nalin; Francesca Pavone; Simone Spada; David G. Trist; Angela Worby
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Journal of Medicinal Chemistry | 2010
Fabrizio Micheli; Paolo Cavanni; Roberto Arban; Roberto Benedetti; Barbara Bertani; Michela Bettati; Letizia Bettelini; Giorgio Bonanomi; Simone Braggio; Anna Checchia; Silvia Davalli; Romano Di Fabio; Elettra Fazzolari; Stefano Fontana; Carla Marchioro; Doug Minick; Michele Negri; Beatrice Oliosi; Kevin D. Read; Ilaria Sartori; Giovanna Tedesco; Luca Tarsi; Silvia Terreni; Filippo Visentini; Alessandro Zocchi; Laura Zonzini
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Journal of Medicinal Chemistry | 2010
Fabrizio Micheli; Luca Arista; Barbara Bertani; Simone Braggio; Anna Maria Capelli; Susanna Cremonesi; Romano Di-Fabio; Giacomo Gelardi; Gabriella Gentile; Carla Marchioro; Alessandra Pasquarello; Stefano Provera; Giovanna Tedesco; Luca Tarsi; Silvia Terreni; Angela Worby; Christian Heidbreder
A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.
Bioorganic & Medicinal Chemistry Letters | 2008
Fabrizio Micheli; Giorgio Bonanomi; Simone Braggio; Anna Maria Capelli; Paolo Celestini; Federica Damiani; Romano Di Fabio; Daniele Donati; Stefania Gagliardi; Gabriella Gentile; Dieter Hamprecht; Marcella Petrone; Stefano Radaelli; Giovanna Tedesco; Silvia Terreni; Angela Worby; Christian Heidbreder
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Journal of Chromatography B | 2010
Nicola Cesari; Stefano Fontana; Dino Montanari; Simone Braggio
Amphetamines are a group of sympathomimetic drugs that exhibit strong central nervous system stimulant effects. D-Amphetamine ((+)-alpha-methylphenetylamine) is the parent drug in this class to which all others are structurally related. In drug discovery, d-amphetamine is extensively used either for the exploration of novel mechanisms involving the catecholaminergic system, or for the validation of new behavioural animal models. Due to this extensive use of D-amphetamine in drug research and its interest in toxicologic-forensic investigation, a specific and high-throughput method, with minimal sample preparation, is necessary for routine analysis of D-amphetamine in biological samples. We propose here a sensitive, specific and high-throughput bioanalytical method for the quantitative determination of D-amphetamine in rat blood using MS(3) scan mode on a hybrid triple quadrupole-linear ion trap mass spectrometer (LC-MS/MS/MS). Blood samples, following dilution with water, were prepared by fully automated protein precipitation with acetonitrile containing an internal standard. The chromatographic separation was achieved on a Waters XTerra C18 column (2.1mm x 30mm, 3.5microm) using gradient elution at a flow rate of 1.0mL/min over a 2min run time. An Applied Biosystems API4000 QTRAP mass spectrometer equipped with turbo ion-spray ionization source was operated simultaneously in MS(3) scan mode for the d-amphetamine and in multiple reaction monitoring (MRM) for the internal standard. The MS/MS/MS ion transition monitored was m/z 136.1-->119.1-->91.1 for the quantitation of d-amphetamine and for the internal standard (rolipram) the MS/MS ion transition monitored was m/z 276.1-->208.2. The linear dynamic range was established over the concentration range 0.5-1000ng/mL (r(2)=0.9991). The method was rugged and sensitive with a lower limit of quantification (LLOQ) of 0.5ng/mL. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. This method was successfully applied to evaluate the pharmacokinetics of d-amphetamine in rat. On a more general extent, this work demonstrated that the selectivity of the fragmentation pathway (MS(3)) can be used as alternative approach to significantly improve detection capability in complex situation (e.g., small molecules in complex matrices) rather than increasing time for sample preparation and chromatographic separation.