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Dive into the research topics where Sonia Maria Poli is active.

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Featured researches published by Sonia Maria Poli.


Journal of Biological Chemistry | 1999

Endogenous proteins controlling amyloid beta-peptide polymerization. Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues.

Bernd Bohrmann; Lars O. Tjernberg; Pascal Kuner; Sonia Maria Poli; Bernard Levet-Trafit; Jan Näslund; Grayson Richards; Walter Huber; Heinz Döbeli; Christer Nordstedt

We report that certain plasma proteins, at physiological concentrations, are potent inhibitors of amyloid β-peptide (Aβ) polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on Aβ. Thirteen proteins representing more than 90% of the protein content in plasma and cerebrospinal fluid were studied. Quantitatively, albumin was the most important protein, representing 60% of the total amyloid inhibitory activity, followed by α1-antitrypsin and immunoglobulins A and G. Albumin suppressed amyloid formation by binding to the oligomeric or polymeric Aβ, blocking a further addition of peptide. This effect was also observed when the incorporation of labeled Aβ into genuine β-amyloid in tissue section was studied. The Aβ and the anti-diabetic drug tolbutamide apparently bind to the same site on albumin. Tolbutamide displaces Aβ from albumin, increasing its free concentration and enhancing amyloid formation. The present results suggest that several endogenous proteins are negative regulators of amyloid formation. Plasma contains at least 300 times more amyloid inhibitory activity than cerebrospinal fluid. These findings may provide one explanation as to why β-amyloid deposits are not found in peripheral tissues but are only found in the central nervous system. Moreover, the data suggest that some drugs that display an affinity for albumin may enhance β-amyloid formation and promote the development of Alzheimer’s disease.


Journal of Pharmacology and Experimental Therapeutics | 2012

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Emmanuel Le Poul; Christelle Bolea; Françoise Girard; Sonia Maria Poli; Delphine Charvin; Brice Campo; Julien Bortoli; Abdhelak Bessif; Bin Luo; Amy Jo Koser; Lisa M. Hodge; Karen M. Smith; Anthony G. DiLella; Nigel J. Liverton; Fred Hess; Susan E. Browne; Ian J. Reynolds

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinsons disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC50 values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of >50-fold the in vitro EC50 value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of l-DOPA (6 mg/kg) enabled a robust, dose-dependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of l-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of l-DOPA was not associated with an exacerbation of l-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinsons disease.


Journal of Pharmacology and Experimental Therapeutics | 2013

ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization

Mikhail Kalinichev; Mélanie Rouillier; Françoise Girard; Isabelle Royer-Urios; Bruno Bournique; Terry Patrick Finn; Delphine Charvin; Brice Campo; Emmanuel Le Poul; Vincent Mutel; Sonia Maria Poli; Stuart A. Neale; T.E. Salt; Robert Johannes Lütjens

Metabotropic glutamate receptor 7 (mGlu7) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu7 negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of l-(+)-2-amino-4-phosphonobutyric acid–induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/total plasma concentration ratio at Cmax = 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamine–induced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu7 and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu7 is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.


Journal of Pharmacology and Experimental Therapeutics | 2014

Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders.

Mikhail Kalinichev; Emmanuel Le Poul; Christelle Bolea; Françoise Girard; Brice Campo; Massimiliano Fonsi; Isabelle Royer-Urios; Susan E. Browne; Jason M. Uslaner; Matthew J. Davis; Jacob Raber; Robert M. Duvoisin; Simon Bate; Ian J. Reynolds; Sonia Maria Poli; Sylvain Celanire

There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]–induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.


Journal of Medicinal Chemistry | 2014

Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

José M. Cid; Gary Tresadern; Guillaume Albert Jacques Duvey; Robert Johannes Lütjens; Terry Patrick Finn; Jean-Philippe Rocher; Sonia Maria Poli; Juan Antonio Vega; Ana Isabel de Lucas; Encarnación Matesanz; María Lourdes Linares; José Ignacio Andrés; Jesús Alcázar; José Manuel Alonso; Gregor James Macdonald; Daniel Oehlrich; Hilde Lavreysen; Abdelah Ahnaou; Wilhelmus Drinkenburg; Claire Mackie; Stefan Pype; David Gallacher; Andrés A. Trabanco

We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.


Journal of Medicinal Chemistry | 2012

Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

José M. Cid; Guillaume Albert Jacques Duvey; Gary Tresadern; Vanthea Nhem; Rocco Furnari; Philippe Cluzeau; Juan Antonio Vega; Ana Isabel de Lucas; Encarnación Matesanz; José Manuel Alonso; María Lourdes Linares; José Ignacio Andrés; Sonia Maria Poli; Robert Johannes Lütjens; Hassan Himogai; Jean-Philippe Rocher; Gregor James Macdonald; Daniel Oehlrich; Hilde Lavreysen; Abdelah Ahnaou; Wilhelmus Drinkenburg; Claire Mackie; Andrés A. Trabanco

The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.


Bioorganic & Medicinal Chemistry Letters | 2011

New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones.

Andrés A. Trabanco; Guillaume Albert Jacques Duvey; José María Cid; Gregor James Macdonald; Philippe Cluzeau; Vanthea Nhem; Rocco Furnari; Nadia Behaj; Géraldine Poulain; Terry Patrick Finn; Hilde Lavreysen; Sonia Maria Poli; Alexandre Raux; Yves Thollon; Nicolas Poirier; David D’Addona; José Ignacio Andrés; Robert Johannes Lütjens; Emmanuel Le Poul; Hassan Julien Imogai; Jean-Philippe Rocher

A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.


Biology of Reproduction | 2014

Inhibition of Follicle-Stimulating Hormone Induced Preovulatory Follicles in Rats Treated with a Nonsteroidal Negative Allosteric Modulator of Follicle-Stimulating Hormone Receptor

James A. Dias; Brice Campo; Barbara A. Weaver; Julie Watts; Kerri Kluetzman; Richard M. Thomas; Beatrice Bonnet; Vincent Mutel; Sonia Maria Poli

ABSTRACT We previously described a negative allosteric modulator (NAM) of FSHR (ADX61623) that blocked FSH-induced cAMP and progesterone production but did not block estradiol production. That FSHR NAM did not affect FSH-induced preovulatory follicle development as evidenced by the lack of an effect on the number of FSH-dependent oocytes found in the ampullae following ovulation with hCG. A goal is the development of a nonsteroidal contraceptive. Toward this end, a high-throughput screen using human FSHR identified an additional nonsteroidal small molecule (ADX68692). Although ADX68692 behaved like ADX61623 in inhibiting production of cAMP and progesterone, it also inhibited FSH-induced estradiol in an in vitro rat granulosa primary cell culture bioassay. When immature, noncycling female rats were injected subcutaneously or by oral dosing prior to exogenous FSH administration, it was found that ADX68692 decreased the number of oocytes recovered from the ampullae. The estrous cycles of mature female rats were disrupted by administration by oral gavage of 25 mg/kg and 10 mg/kg ADX68692. In the highest dose tested (25 mg/kg), 55% of animals cohabited with mature males had implantation sites compared to 33% in the 10 mg/kg group and 77% in the control group. A surprising finding was that a structural analog ADX68693, while effectively blocking progesterone production with similar efficacy as ADX68692, did not block estrogen production and despite better oral availability did not decrease the number of oocytes found in the ampullae even when used at 100 mg/kg. These data demonstrate that because of biased antagonism of the FSHR, nonsteroidal contraception requires that both arms of the FSHR steroidogenic pathway must be effectively blocked, particularly estrogen biosynthesis. Thus, a corollary to these findings is that it seems reasonable to propose that the estrogen-dependent diseases such as endometriosis may benefit from inhibition of FSH action at the ovary using the FSHR NAM approach.


Drug Development and Industrial Pharmacy | 2013

Amorphous solid dispersion successfully improved oral exposure of ADX71943 in support of toxicology studies.

Mohamad Haitham Ayad; Beatrice Bonnet; Jacques Quinton; Matthew Louis Steven Leigh; Sonia Maria Poli

ADX71943 is a potent and selective GABAb receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability. Both technologies have proven useful in improving the in vitro dissolution profile and as a result of the solubility enhancement, higher bioavailability was obtained in vivo. As the solid dispersion gave better bioavailability (30-fold compared with the neat active pharmaceutical ingredient (API)), this formulation was selected for the toxicology study. Changing the crystalline form of ADX71943 into amorphous state by preparing a solid dispersion has greatly improved its oral bioavailability and has allowed achieving the required plasma concentration needed in toxicology studies.


Bioorganic & Medicinal Chemistry Letters | 2010

Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.

Jens-Uwe Peters; Torsten Hoffmann; Patrick Schnider; Heinz Stadler; Andreas Koblet; André Alker; Sonia Maria Poli; Theresa M. Ballard; Will Spooren; Lucinda Steward; Andrew Sleight

During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.

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Emmanuel Le Poul

Université libre de Bruxelles

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