Publications (21)65.8 Total impact
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Article: 5-Aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK-3 inhibitors.
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ABSTRACT: 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.Bioorganic & medicinal chemistry letters 03/2012; 22(5):1989-94. · 2.65 Impact Factor -
Article: Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors.
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ABSTRACT: 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.Bioorganic & medicinal chemistry letters 08/2011; 21(16):4823-7. · 2.65 Impact Factor -
Article: Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists.
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ABSTRACT: 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.Journal of Medicinal Chemistry 10/2010; 53(19):7129-39. · 4.80 Impact Factor -
Article: [3-azabicyclo[3.1.0]hex-1-yl]phenyl-benzenesulfonamides as selective dopamine D3 antagonists.
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ABSTRACT: A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D3 antagonists together with SAR and selectivity data.Bioorganic & medicinal chemistry letters 09/2010; 20(18):5491-4. · 2.65 Impact Factor -
Article: Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: novel, potent, and selective series of Vasopressin 1b receptor antagonists.
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ABSTRACT: 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.Bioorganic & medicinal chemistry letters 09/2010; 20(17):5044-9. · 2.65 Impact Factor -
Article: 1,2,4-Triazolyl azabicyclo[3.1.0]hexanes: a new series of potent and selective dopamine D(3) receptor antagonists.
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ABSTRACT: 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.Journal of Medicinal Chemistry 11/2009; 53(1):374-91. · 4.80 Impact Factor -
Article: Dopamine D3 receptor antagonists: the quest for a potentially selective PET ligand. Part 3: Radiosynthesis and in vivo studies.
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ABSTRACT: Compound 1 is a potent and selective antagonist of the dopamine D(3) receptor. With the aim of developing a carbon-11 labeled ligand for the dopamine D(3) receptor, 1 was selected as a potential PET probe. [(11)C]1 was obtained by palladium catalyzed cross coupling using [(11)C]cyanide and 4 with a specific activity of 55.5+/-25.9GBq/micromol (1.5+/-0.7Ci/micromol). [(11)C]1 was tested in porcine and non-human primate models to assess its potential as a radioligand for PET imaging of the dopamine D(3) receptor. We conclude that in both species and despite appropriate in vitro properties, [(11)C]1 does not show any specific signal for the dopamine D(3) receptor.Bioorganic & medicinal chemistry letters 08/2009; 19(17):5056-9. · 2.65 Impact Factor -
Article: In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: Studies in non-human primates and transgenic mice.
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ABSTRACT: Examination of dopamine-D3 (D3) receptors with positron emission tomography (PET) have been hampered in the past by the lack of a PET ligand with sufficient selectivity for D3 over dopamine-D2 (D2) receptors. The two types co-localize in the brain, with D2 density significantly higher than D3, hence nonselective PET ligands inform on D2, rather than D3 status. [(11)C]-(+)-PHNO is a novel PET ligand with a preferential affinity for D3 over D2. We used the selective D3 antagonist, SB-277011 to dissect regional fractions of the [(11)C]-(+)-PHNO signal attributable to D3 and D2 in primate brain. The results were compared with quantitative autoradiography with (3)H-(+)-PHNO in wild-type, D2-knock-out, and D3-knock-out mice examined at baseline and following administration of SB-277011. Both sets of results converged to indicate a predominant D3-related component to (+)-PHNO binding in extra-striatal regions, with binding in the midbrain being entirely attributable to D3. The midbrain is thus an excellent target region to examine D3 receptor occupancy with [(11)C]-(+)-PHNO PET in vivo.Synapse 07/2009; 63(9):782-93. · 2.94 Impact Factor -
Article: Dopamine D3 receptor antagonists: the quest for a potentially selective PET ligand. Part one: lead identification.
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ABSTRACT: The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.Bioorganic & medicinal chemistry letters 07/2009; 19(16):4799-801. · 2.65 Impact Factor -
Article: Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization.
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ABSTRACT: The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.Bioorganic & medicinal chemistry letters 07/2009; 19(15):4011-3. · 2.65 Impact Factor -
Article: Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies.
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ABSTRACT: In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.Journal of Medicinal Chemistry 12/2008; 51(22):7273-86. · 4.80 Impact Factor -
Article: Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.
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ABSTRACT: 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 12/2008; 51(23):7370-9. · 4.80 Impact Factor -
Article: New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part one: [h]-fused tricyclic systems.
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ABSTRACT: 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.Bioorganic & medicinal chemistry letters 03/2008; 18(3):901-7. · 2.65 Impact Factor -
Article: Heteroaryl-substituted 4-(1H-pyrazol-1-yl)-5,6-dihydro-1H-pyrrolo[2,3-d]pyrimidine derivatives as potent and selective corticotropin-releasing factor receptor-1 antagonists.
ChemMedChem 03/2008; 3(2):226-9. · 3.15 Impact Factor -
Article: New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part 2: [g]-fused and hetero-fused systems.
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ABSTRACT: The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.Bioorganic & medicinal chemistry letters 03/2008; 18(3):908-12. · 2.65 Impact Factor -
Article: Heteroaryl‐Substituted 4‐(1H‐pyrazol‐1‐yl)‐5,6‐dihydro‐1H‐pyrrolo[2,3‐d]pyrimidine Derivatives as Potent and Selective Corticotropin‐Releasing Factor Receptor‐1 Antagonists
ChemMedChem 11/2007; 3(2):226 - 229. · 3.15 Impact Factor -
Article: 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.
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ABSTRACT: The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.Journal of Medicinal Chemistry 11/2007; 50(21):5076-89. · 5.25 Impact Factor -
Article: Novel substituted tetrahydrotriazaacenaphthylene derivatives as potent CRF1 receptor antagonists.
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ABSTRACT: Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.Bioorganic & Medicinal Chemistry Letters 10/2007; 17(18):5218-21. · 2.55 Impact Factor -
Article: 1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: A Series of Potent and Selective Dopamine D3 Receptor Antagonists
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ABSTRACT: The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.09/2007; -
Article: Cyclopenta[d]pyrimidines and dihydropyrrolo[2,3-d]pyrimidines as potent and selective corticotropin-releasing factor 1 receptor antagonists.
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ABSTRACT: Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.ChemMedChem 05/2007; 2(4):528-40. · 3.15 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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Aptuit - Drug Development Services & Drug Discovery
Greenwich, CT, USA
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2009
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Cancer Australia
Surrey Hills, Victoria, Australia
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2007–2009
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GlaxoSmithKline plc.
- Department of Medicinal Chemistry
London, ENG, United Kingdom
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