Publications by authors named "Giuseppe Alvaro"

31 Publications

Effect of Kv3 channel modulators on auditory temporal resolution in aged Fischer 344 rats.

Hear Res 2021 Mar 8;401:108139. Epub 2020 Dec 8.

Department of Auditory Neuroscience, Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic.

AUT00063 and AUT00202 are novel pharmaceutical modulators of the Kv3 subfamily of voltage-gated K channels. Kv3.1 channels, which control fast firing of many central auditory neurons, have been shown to decline with age and this may contribute to age-related deficits in central auditory processing. In the present study, the effects of the two novel compounds that specifically modulate Kv3 channels on auditory temporal processing were examined in aged (19-25-month-old) and young-adult (3-5 month-old) Fischer 344 rats (F344) using a behavioral gap-prepulse inhibition (gap-PPI) paradigm. The acoustic startle response (ASR) and its inhibition induced by a gap in noise were measured before and after drug administration. Hearing thresholds in tested rats were evaluated by the auditory brainstem response (ABR). Aged F344 rats had significantly higher ABR thresholds, lower amplitudes of ASR, and weaker gap-PPI compared with young-adult rats. No influence of AUT00063 and AUT00202 administration was observed on ABR hearing thresholds in rats of both age groups. AUT00063 and AUT00202 had suppressive effect on ASR of F344 rats that was more pronounced with AUT00063. The degree of suppression depended on the dose and age of the rats. Both compounds significantly improved the gap-PPI performance in gap detection tests in aged rats. These results indicate that AUT00063 and AUT00202 may influence intrinsic firing properties of neurons in the central auditory system of aged animals and have the potential to treat aged-related hearing disorders.
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http://dx.doi.org/10.1016/j.heares.2020.108139DOI Listing
March 2021

Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

ACS Med Chem Lett 2020 Sep 16;11(9):1678-1687. Epub 2020 Jul 16.

Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.

Drugs that block voltage-gated sodium channels (Nas) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved Na blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488392PMC
September 2020

Effectiveness of Risk Minimization Measures to Prevent Pregnancy Exposure to Mycophenolate-Containing Medicines in Europe.

Pharmaceut Med 2019 10;33(5):395-406

Safety Risk Management, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Introduction: In 2015, the European Medicines Agency (EMA) requested additional Risk Minimization Measures (RMM), consisting of a Direct Healthcare Professional Communication (DHPC), a Guide for Healthcare Professionals (HCPs), and a Guide for Patients, to prevent pregnancy exposure to mycophenolate-containing medicines.

Objectives: This study assessed the effectiveness of the additional RMM for any mycophenolate-containing medicine among prescribers of these products in Europe.

Methods: A cross-sectional survey was conducted among prescribers of mycophenolate-containing medicines in five European countries via the administration of 19 questions checking knowledge levels for the key messages included in the additional RMM.

Results: Of 79,783 invitations sent to potential prescribers of mycophenolate-containing medicines, 295 HCPs accessed the survey, giving an overall response rate of 0.4% (range 0.1-8.6%). A total of 231 prescribers were included in the primary analysis. Knowledge levels for 15 questions was fair (50 to < 70%) to high (≥ 70%), and for 4 questions was poor (< 50%). Highest knowledge (≥ 75%) was for knowing that mycophenolate is contraindicated in women of childbearing potential not using highly effective contraception (80.3%) and that mycophenolate should not be routinely prescribed during pregnancy (77.5%). Lowest knowledge (≤ 30%) was for knowing that no specific mechanism of teratogenicity and mutagenicity has been identified for mycophenolate (23.4%). Less than half of HCPs reported receipt of the DHPC (42.5%) or were aware of the Guide for HCPs (32.1%) and Guide for Patients (29.7%). The most frequently reported primary source from which HCPs learned about these risks was the Summary of Product Characteristics (SmPC; 33.8%), while only 9.9% indicated the Guide for HCPs.

Conclusion: Prescribers who participated in this survey appear to be reasonably well informed about the key messages of the RMM put in place in Europe for mycophenolate-containing medicines. The relatively high knowledge levels, in spite of the low proportion of HCPs reporting receipt of the additional RMM, suggest that the SmPC may be sufficiently informing prescribers about the pregnancy risks of mycophenolate-containing medicines and actions recommended to minimize pregnancy risk. Nevertheless, Roche in consultation with EMA will continue to distribute all additional RMM.
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http://dx.doi.org/10.1007/s40290-019-00304-0DOI Listing
October 2019

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice.

J Neurosci 2019 06 1;39(24):4797-4813. Epub 2019 Apr 1.

Departments of Pharmacology,

Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded in mice lacking the gene ( ) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K currents that activate at positive potentials ("high-threshold" K currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in mice, while K currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 [((4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile], a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K current and increased the low-threshold K currents in neurons from animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and, , restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS. mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses , suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.
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http://dx.doi.org/10.1523/JNEUROSCI.0839-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561694PMC
June 2019

Pediatric Dosing of Ganciclovir and Valganciclovir: How Model-Based Simulations Can Prevent Underexposure and Potential Treatment Failure.

CPT Pharmacometrics Syst Pharmacol 2019 03 18;8(3):167-176. Epub 2018 Dec 18.

Pharma Research & Development, Pharmaceutical Sciences-Clinical Pharmacology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens are used in medical practice. Population pharmacokinetic (PopPK) model-based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg = 7 × body surface area (BSA) × creatinine clearance according to the Schwarz formula (CrCLS) daily) and i.v. ganciclovir (mg = 3 × BSA × CrCLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (area under the concentration-time curve (AUC) 40-60 μg ∙ hour/mL) in most pediatric patients across the full pediatric age range. In contrast, ganciclovir and valganciclovir dosing based on body weight, as commonly used in medical practice, leads to underexposure, particularly in younger pediatric patients. This example shows that model-based dosing algorithms built on clinical pharmacology and implemented using good modeling practice can prevent underexposure and reduce the risk of treatment failure in pediatric patients.
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http://dx.doi.org/10.1002/psp4.12363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430157PMC
March 2019

Increased spontaneous firing rates in auditory midbrain following noise exposure are specifically abolished by a Kv3 channel modulator.

Hear Res 2018 08 30;365:77-89. Epub 2018 Apr 30.

Ear Institute, University College London, 332 Gray's Inn Road, London, WC1X 8EE, UK; Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. Electronic address:

Noise exposure has been shown to produce long-lasting increases in spontaneous activity in central auditory structures in animal models, and similar pathologies are thought to contribute to clinical phenomena such as hyperacusis or tinnitus in humans. Here we demonstrate that multi-unit spontaneous neuronal activity in the inferior colliculus (IC) of mice is significantly elevated four weeks following noise exposure at recording sites with frequency tuning within or near the noise exposure band, and this selective central auditory pathology can be normalised through administration of a novel compound that modulates activity of Kv3 voltage-gated ion channels. The compound had no statistically significant effect on IC spontaneous activity without noise exposure, nor on thresholds or frequency tuning of tone-evoked responses either with or without noise exposure. Administration of the compound produced some reduction in the magnitude of evoked responses to a broadband noise, but unlike effects on spontaneous rates, these effects on evoked responses were not specific to recording sites with frequency tuning within the noise exposure band. Thus, the results suggest that modulators of Kv3 channels can selectively counteract increases in spontaneous activity in the auditory midbrain associated with noise exposure.
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http://dx.doi.org/10.1016/j.heares.2018.04.012DOI Listing
August 2018

Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus.

Hear Res 2018 04 7;361:36-44. Epub 2018 Feb 7.

Department of Neurosciences, Lerner Research Institute, Head and Neck Institute, Cleveland Clinic, USA. Electronic address:

The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a floor level that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.
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http://dx.doi.org/10.1016/j.heares.2018.01.017DOI Listing
April 2018

Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator.

Neuropsychopharmacology 2018 Jan 31;43(2):435-444. Epub 2017 Aug 31.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.
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http://dx.doi.org/10.1038/npp.2017.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729564PMC
January 2018

Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons.

J Neurophysiol 2016 07 6;116(1):106-21. Epub 2016 Apr 6.

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;

Many rapidly firing neurons, including those in the medial nucleus of the trapezoid body (MNTB) in the auditory brain stem, express "high threshold" voltage-gated Kv3.1 potassium channels that activate only at positive potentials and are required for stimuli to generate rapid trains of actions potentials. We now describe the actions of two imidazolidinedione derivatives, AUT1 and AUT2, which modulate Kv3.1 channels. Using Chinese hamster ovary cells stably expressing rat Kv3.1 channels, we found that lower concentrations of these compounds shift the voltage of activation of Kv3.1 currents toward negative potentials, increasing currents evoked by depolarization from typical neuronal resting potentials. Single-channel recordings also showed that AUT1 shifted the open probability of Kv3.1 to more negative potentials. Higher concentrations of AUT2 also shifted inactivation to negative potentials. The effects of lower and higher concentrations could be mimicked in numerical simulations by increasing rates of activation and inactivation respectively, with no change in intrinsic voltage dependence. In brain slice recordings of mouse MNTB neurons, both AUT1 and AUT2 modulated firing rate at high rates of stimulation, a result predicted by numerical simulations. Our results suggest that pharmaceutical modulation of Kv3.1 currents represents a novel avenue for manipulation of neuronal excitability and has the potential for therapeutic benefit in the treatment of hearing disorders.
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http://dx.doi.org/10.1152/jn.00174.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961756PMC
July 2016

Paediatric musculoskeletal interventional radiology.

Br J Radiol 2016 23;89(1057):20150369. Epub 2015 Sep 23.

1 Interventional Radiology Unit, "Bambino Gesù" Children's Hospital, Rome, Italy.

Interventional radiology technique is now well established and widely used in the adult population. Through minimally invasive procedures, it increasingly replaces surgical interventions that involve higher percentages of invasiveness and, consequently, of morbidity and mortality. For these advantageous reasons, interventional radiology in recent years has spread to the paediatric age as well. The aim of this study was to review the literature on the development, use and perspectives of these procedures in the paediatric musculoskeletal field. Several topics are covered: osteomuscle neoplastic malignant and benign pathologies treated with invasive diagnostic and/or therapeutic procedures such as radiofrequency ablation in the osteoid osteoma; invasive and non-invasive procedures in vascular malformations; treatment of aneurysmal bone cysts; and role of interventional radiology in paediatric inflammatory and rheumatic inflammations. The positive results that have been generated with interventional radiology procedures in the paediatric field highly encourage both the development of new ad hoc materials, obviously adapted to young patients, as well as the improvement of such techniques, in consideration of the fact that childrens' pathologies do not always correspond to those of adults. In conclusion, as these interventional procedures have proven to be less invasive, with lower morbidity and mortality rates as well, they are becoming a viable and valid alternative to surgery in the paediatric population.
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http://dx.doi.org/10.1259/bjr.20150369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985951PMC
May 2016

A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons.

J Pharmacol Exp Ther 2015 Sep 17;354(3):251-60. Epub 2015 Jun 17.

Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.)

Kv3.1 and Kv3.2 high voltage-activated potassium channels, which display fast activation and deactivation kinetics, are known to make a crucial contribution to the fast-spiking phenotype of certain neurons. Pharmacological experiments show that the blockade of native Kv3 currents with low concentrations of tetraethylammonium or 4-aminopyridine impairs the expression of this firing phenotype. In particular, Kv3 channels are highly expressed by fast-spiking, parvalbumin-positive interneurons in corticolimbic brain circuits, which modulate the synchronization of cortical circuits and the generation of brain rhythms. Here, we describe a novel small molecule, (5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione (AUT1), which modulates Kv3.1 and Kv3.2 channels in human recombinant and rodent native neurons. AUT1 increased whole currents mediated by human Kv3.1b and Kv3.2a channels, with a concomitant leftward shift in the voltage dependence of activation. A less potent effect was observed on hKv3.3 currents. In mouse somatosensory cortex slices in vitro, AUT1 rescued the fast-spiking phenotype of parvalbumin-positive-fast-spiking interneurons following an impairment of their firing capacity by blocking a proportion of Kv3 channels with a low concentration of tetraethylammonium. Notably, AUT1 had no effect on interneuron firing when applied alone. Together, these data confirm the role played by Kv3 channels in the regulation of the firing phenotype of somatosensory interneurons and suggest that AUT1 and other Kv3 modulators could represent a new and promising therapeutic approach to the treatment of disorders associated with dysfunction of inhibitory feedback in corticolimbic circuits, such as schizophrenia.
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http://dx.doi.org/10.1124/jpet.115.225748DOI Listing
September 2015

Colon capsule versus CT colonography in patients with incomplete colonoscopy: a prospective, comparative trial.

Gut 2015 Feb 24;64(2):272-81. Epub 2014 Jun 24.

Digestive Endoscopy Unit, Catholic University, Rome, Italy.

Objective: In case of incomplete colonoscopy, several radiologic methods have traditionally been used, but more recently, capsule endoscopy was also shown to be accurate. Aim of this study was to compare colon capsule endoscopy (CCE) and CT colonography (CTC) in a prospective cohort of patients with incomplete colonoscopy.

Design: Consecutive patients with a previous incomplete colonoscopy underwent CCE and CTC followed by colonoscopy in case of positive findings on either test (polyps/mass lesions ≥6 mm). Clinical follow-up was performed in the other cases to rule out missed cancer. CTC was performed after colon capsule excretion or 10-12 h postingestion. Since the gold standard colonoscopy was performed only in positive cases, diagnostic yield and positive predictive values of CCE and CTC were used as study end-points.

Results: 100 patients were enrolled. CCE and CTC were able to achieve complete colonic evaluation in 98% of cases. In a per-patient analysis for polyps ≥6 mm, CCE detected 24 patients (24.5%) and CTC 12 patients (12.2%). The relative sensitivity of CCE compared to CTC was 2.0 (95% CI 1.34 to 2.98), indicating a significant increase in sensitivity for lesions ≥6 mm. Of larger polyps (≥10 mm), these values were 5.1% for CCE and 3.1% for CTC (relative sensitivity: 1.67 (95% CI 0.69 to 4.00)). Positive predictive values for polyps ≥6 mm and ≥10 mm were 96% and 85.7%, and 83.3% and 100% for CCE and CTC, respectively. No missed cancer occurred at clinical follow-up of a mean of 20 months.

Conclusions: CCE and CTC were of comparable efficacy in completing colon evaluation after incomplete colonoscopy; the overall diagnostic yield of colon capsule was superior to CTC.

Trial Registration Number: NCT01525940.
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http://dx.doi.org/10.1136/gutjnl-2013-306550DOI Listing
February 2015

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

Bioorg Med Chem 2013 Nov 11;21(21):6264-73. Epub 2013 Sep 11.

Neurosciences Centre of Excellence for Drug Discovery, Chemical Development and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bmc.2013.09.001DOI Listing
November 2013

Hepatic veins in presurgical planning of hepatic resection: what a radiologist should know.

Abdom Imaging 2013 Jun;38(3):442-60

Department of Bioimaging and Radiological Sciences, School of Medicine, Catholic University, Largo A. Gemelli 1, Rome, Italy.

Hepatic resection is considered to be feasible when all malignant nodules can be technically excised. The goal of the surgical approach is to optimize the oncologic resection (negative margins), sparing the non-cancerous hepatic parenchyma. The outflowing hepatic vein (HV) of that particular liver remnant must be intact in order to preserve its function. The purpose of this article is to familiarize radiologists with anatomy and anatomical variants of HVs, with special emphasis on segmental venous drainage for presurgical planning of hepatic resections. We focus on information which radiologist should give to hepatic surgeon to choose proper surgical approach. Radiologist's familiarity with the anatomy and anatomical variants of HVs is essential for accurate surgical planning to avoid venous congestion as postoperative complication. Any clinically important hepatic vein variation detected on presurgical imaging should be carefully recorded in the radiology report.
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http://dx.doi.org/10.1007/s00261-012-9900-8DOI Listing
June 2013

Identification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia.

Bioorg Med Chem Lett 2011 Nov 6;21(22):6899-904. Epub 2011 Aug 6.

GlaxoSmithKline Medicines Research Centre, Neurosciences Centre of Excellence for Drug Discovery, Via Fleming 4, 37135 Verona, Italy.

During the lead optimization of NK(1)/NK(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK(1) and NK(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK(1)/NK(3) activity, were reported in this paper.
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http://dx.doi.org/10.1016/j.bmcl.2011.07.116DOI Listing
November 2011

The efficacy of sodium channel blockers to prevent phencyclidine-induced cognitive dysfunction in the rat: potential for novel treatments for schizophrenia.

J Pharmacol Exp Ther 2011 Jul 12;338(1):100-13. Epub 2011 Apr 12.

Neuroscience Centre of Excellence for Drug Discovery, Medicines Research Centre, GlaxoSmithKline SpA., Verona, Italy.

Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug's efficacy in patients with schizophrenia has not been possible. (5R)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-l-prolinamide (GSK2) and (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (GSK3) are two new structurally diverse sodium channel blockers with potent anticonvulsant activity. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-d-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication.
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http://dx.doi.org/10.1124/jpet.110.178475DOI Listing
July 2011

Discovery and biological characterization of (2R,4S)-1'-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4'-bipiperidine-1-carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate.

J Med Chem 2011 Feb 13;54(4):1071-9. Epub 2011 Jan 13.

GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.
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http://dx.doi.org/10.1021/jm1013264DOI Listing
February 2011

Application of LC-NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant).

Magn Reson Chem 2010 Jul;48(7):523-30

Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.

Liquid chromatography-NMR (LC-NMR) spectroscopy was used to obtain detailed information regarding the structure of the major bulk drug impurities present in GW597599 (vestipitant). The one-dimensional (1)H LC-NMR experiments were performed in both continuous and stop-flow modes on a sample of GW597599 (vestipitant) enriched with mother liquor impurities. The information derived from both LC-NMR and LC-MS data provided the structural information of all major impurities. The full characterisation of the impurities by high-resolution NMR spectroscopy was ultimately performed on appropriately synthesised compounds.
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http://dx.doi.org/10.1002/mrc.2611DOI Listing
July 2010

Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat.

Epilepsia 2010 Aug 7;51(8):1543-51. Epub 2010 Jan 7.

New Frontiers Science Park, GlaxoSmithKline plc, Harlow, Essex, UK.

Purpose: Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.

Methods: Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.

Results: The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.

Discussion: These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.
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http://dx.doi.org/10.1111/j.1528-1167.2009.02482.xDOI Listing
August 2010

Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK(1) receptor antagonists.

Bioorg Med Chem Lett 2010 Jan 20;20(2):623-7. Epub 2009 Nov 20.

Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.

A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.
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http://dx.doi.org/10.1016/j.bmcl.2009.11.078DOI Listing
January 2010

Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist.

J Med Chem 2009 May;52(10):3238-47

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.

In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.
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http://dx.doi.org/10.1021/jm900023bDOI Listing
May 2009

The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat.

Epilepsy Res 2009 Jul 28;85(1):96-106. Epub 2009 Mar 28.

epartment of Molecular and Cellular Biology, Neuroscience Centre of Excellence for Drug Discovery, Medicines Research Centre, GlaxoSmithKline S.p.A., Via Fleming 4, Verona 37135, Italy.

The development of novel anticonvulsant drugs with improved efficacy for the treatment of epilepsy is hindered by a lack of information regarding the quantitative relationship between target mechanism and in vivo efficacy. In the present study we have examined the correlation between the potency of structurally diverse compounds at voltage-gated sodium channels in vitro and their efficacy in a rodent model of acute generalised seizures induced by electroshock. We observed a significant correlation between the estimated affinity (Ki) of the compounds for the inactivated state of human recombinant Na(V)1.2 channels and the unbound brain concentration required for anticonvulsant efficacy. Furthermore, the data suggest that an unbound concentration equivalent to less than 50% of the Ki is sufficient for anticonvulsant effect. We noted that increasing sodium channel blocking potency was associated with increasing brain tissue binding and lipophilicity. These data suggest that there is a balance between sodium channel blocking potency in vitro and good pharmacokinetic characteristics necessary for anticonvulsant efficacy in vivo. Finally, we examined the sodium channel blocking potency of sodium valproate in relation to its anticonvulsant efficacy in vivo. We found that a higher unbound concentration of the drug in the brain was required for anticonvulsant efficacy than would be expected given its sodium channel blocking potency.
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http://dx.doi.org/10.1016/j.eplepsyres.2009.02.018DOI Listing
July 2009

[An integrated model for the evaluation and risk management of tuberculosis infection and active tuberculosis in homeless people in the city of Rome (Italy)].

Ig Sanita Pubbl 2008 Jul-Aug;64(4):431-45

Istituto di Igiene, Università Cattolica del Sacro Cuore, Facoltà di Medicina e Chirurgia Agostino Gemelli, Largo Francesco Vito, Roma.

In this article we describe an integrated model for the evaluation and risk management of tuberculosis (TB) infection and active TB in socially disadvantaged populations in the city of Rome. We describe and discuss the clinical evaluation procedures performed and the data collection forms used; these tools are useful for the epidemiologic surveillance and clinical management of patients, particularly high risk patients such as the homeless.
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February 2009

Neurokinin 1 receptor antagonists--current prospects.

Curr Opin Drug Discov Devel 2007 Sep;10(5):613-21

GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy.

The isolation of substance P (SP) in 1931, and the later discovery of its preferred neurokinin (NK)1 receptor, led to an intense research effort aimed at elucidating the biological role of SP, particularly within the central nervous system. There is now a large body of evidence to support the hypothesis that SP is one of the most important neurotransmitters and neuromodulators present in the brain. Its pharmacology has been intimately linked to the pathophysiology of several relevant neurological and psychiatric disorders, namely nociception, migraine, asthma, nausea, inflammatory bowel syndrome, urinary incontinence, anxiety and depression. This wide therapeutic potential triggered an unprecedented research effort, both preclinically and clinically, to identify appropriate NK1 receptor antagonists and transform them into effective drugs. To date, despite huge investments made by some of the largest pharmaceutical groups worldwide, aprepitant (MK-869, an anti-emetic agent) remains the only NK1 receptor antagonist on the market. Nevertheless, the 'NK1 receptor antagonist race' is not over, as witnessed by the significant number of patents and scientific publications claiming the discovery of new NK1 receptor antagonists issued in recent years. This review describes the most relevant results obtained in this field in the period 2005 to 2006.
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September 2007

Asymmetric route to pyridines bearing a highly functionalized 2-alkyl substituent by aziridine ring-opening reactions.

J Org Chem 2007 May 14;72(10):3859-62. Epub 2007 Apr 14.

Dipartimento di Chimica G. Ciamician, Università di Bologna, via Selmi 2, 40126 Bologna, Italy.

The aziridine prepared from the 2-pyridineimine derived from (S)-valinol underwent ring-opening by attack of nitrogen, sulfur, and oxygen nucleophiles. Complete or prevalent regioselectivity was obtained using cerium trichloride heptahydrate as a catalyst. In some cases, the N-substituent could be removed by an oxidative protocol.
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http://dx.doi.org/10.1021/jo070364aDOI Listing
May 2007

From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolines: a new class of orally bioavailable mGluR1 antagonists.

Bioorg Med Chem Lett 2007 Apr 25;17(8):2254-9. Epub 2007 Jan 25.

GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy.

Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.055DOI Listing
April 2007

Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain.

Bioorg Med Chem Lett 2007 Mar 12;17(5):1176-80. Epub 2006 Dec 12.

GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.

Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2006.12.022DOI Listing
March 2007

Asymmetric synthesis of 2-(2-pyridyl)aziridines from 2-pyridineimines bearing stereogenic N-alkyl substituents and regioselective opening of the aziridine ring.

J Org Chem 2006 Dec;71(25):9373-81

Dipartimento di Chimica G. Ciamician, Università di Bologna, via Selmi 2, 40126 Bologna, Italy.

The addition of chloromethyllithium to the imine derived from 2-pyridinecarboxaldehyde and (S)-valinol, protected as its O-trimethylsilyl ether, gave the 1,2-disubstituted aziridine with good yield and diastereoselectivity. The analogous reaction performed on the imine derived from (S)-valine methyl ester gave the product containing the aziridine ring and the alpha-chloro ketone group coming from the attack of chloromethyllithium to the ester function. Other stereogenic alkyl substituents at nitrogen gave less satisfactory results. Moreover, the aziridination protocol did not work on other aromatic imines which were not capable of bidentate chelation, e.g., 3- and 4-pyridineimine and benzaldimine. Preliminary studies showed the possibility to carry out regio- and stereospecific opening reactions of 2-(2-pyridyl)aziridines by attack of internally generated or external nucleophiles.
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http://dx.doi.org/10.1021/jo0614137DOI Listing
December 2006

Enantiomerically pure tetrahydroquinoline derivatives as in vivo potent antagonists of the glycine binding site associated to the NMDA receptor.

Bioorg Med Chem Lett 2003 Nov;13(21):3863-6

Medicines Research Centre, GlaxoSmithKline S.p.A, Via Fleming 4, 37135 Verona, Italy.

To identify neuroprotective agents after stroke, new substituted tetrahydroquinoline derivatives were designed as antagonists of the glycine binding site associated to the NMDA receptor, satisfying the key pharmacophoric requirements. In particular, the racemate 3c exhibited outstanding in vivo activity in the MCAo model in rats, when given iv both pre- and post-ischemia. Pure enantiomers 3c-(+) and 3c-(-) have been prepared following an original synthetic route. Despite the significant difference of activity observed in vitro, they shown similar neuroprotective profile in the MCAo model in rats.
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http://dx.doi.org/10.1016/j.bmcl.2003.06.001DOI Listing
November 2003

Novel stereocontrolled addition of allylmetal reagents to alpha-imino esters: efficient synthesis of chiral tetrahydroquinoline derivatives.

J Org Chem 2002 Oct;67(21):7319-28

Medicines Research Centre, GlaxoSmithKline S.p.A, Via Fleming 4, 37135 Verona, Italy.

To prepare in multigram scale new antagonists of the glycine binding site associated to the NMDA receptor, an efficient distereoselective route was set up. The addition of suitable allyltin reagents to chiral N-aryl alpha-imino esters (R-(+)-tert-butyl lactate used as chiral auxiliary), gave the corresponding alpha amino acid-type derivative in high chemical yield and optical purity. This allylation reaction represents a novel example of efficient long-range stereodifferentiation process. In the last part of the synthesis, a regioselective Heck-type cyclization reaction enabled preparation of the target tetrasubstituted exocycle and trisubtituted endocycle double bond derivatives.
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http://dx.doi.org/10.1021/jo020327dDOI Listing
October 2002