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Märstetten-Dorf, Switzerland

Ayad M.H.,Addex Pharmaceuticals | Bonnet B.,Addex Pharmaceuticals | Quinton J.,Phares AG | Leigh M.,Phares AG | Poli S.M.,Addex Pharmaceuticals
Drug Development and Industrial Pharmacy | Year: 2013

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. © 2013 Informa Healthcare USA, Inc. Source


Trabanco A.A.,Janssen Cilag SAS | Duvey G.,Addex Pharmaceuticals | Cid J.M.,Janssen Cilag SAS | MacDonald G.J.,Janssen Pharmaceutical | And 17 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

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. © 2010 Elsevier Ltd. All rights reserved. Source


Trabanco A.A.,Janssen Cilag SAS | Duvey G.,Addex Pharmaceuticals | Cid J.M.,Janssen Cilag SAS | MacDonald G.J.,Janssen Pharmaceutical | And 17 more authors.
MedChemComm | Year: 2011

A series of N-propyl-5-substituted isoquinolones was identified as positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) via high-throughput screening (HTS). The subsequent synthesis and preliminary SAR exploration that led to the identification of compound 20 are described. © 2011 The Royal Society of Chemistry. Source


Cid J.M.,Janssen Pharmaceutical | Cid J.M.,Spanish National Cancer Research Center | Duvey G.,Addex Pharmaceuticals | Cluzeau P.,Addex Pharmaceuticals | And 27 more authors.
ACS Chemical Neuroscience | Year: 2010

A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice. © 2010 American Chemical Society. Source


Schelshorn D.,Addex Pharmaceuticals | Joly F.,Addex Pharmaceuticals | Mutel S.,Addex Pharmaceuticals | Hampe C.,Addex Pharmaceuticals | And 3 more authors.
Molecular Pharmacology | Year: 2012

Activation of G-protein-coupled receptors (GPCRs) results in a variety of cellular responses, such as binding to the same receptor of different ligands that activate distinct downstream cascades. Additional signaling complexity is achieved when two or more receptors are integrated into one signaling unit. Lateral receptor interactions can allosterically modulate the receptor response to a ligand, which creates a mechanism for tissue-specific fine tuning, depending on the cellular receptor coexpression pattern. GPCR homomers or heteromers have been explored widely for GPCR classes A and C but to lesser extent for class B. In the present study, we used bioluminescence resonance energy transfer (BRET) techniques, calcium flux measurements, and microscopy to study receptor interactions within the glucagon receptor family. We found basal BRET interactions for some of the receptor combinations tested that decreased upon ligand binding. A BRET increase was observed exclusively for the gastric inhibitory peptide (GIP) receptor and the glucagon-like peptide 1 (GLP-1) receptor upon binding of GLP-1 that could be reversed with GIP addition. The interactions of GLP-1 receptor and GIP receptor were characterized with BRET donor saturation studies, shift experiments, and tests of glucagon-like ligands. The heteromer displayed specific pharmacological characteristics with respect to GLP-1-induced β-arrestin recruitment and calcium flux, which suggests a form of allosteric regulation between the receptors. This study provides the first example of ligand-induced heteromer formation in GPCR class B. In the body, the receptors are functionally related and coexpressed in the same cells. The physiological evidence for this heteromerization remains to be determined. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics. Source

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