El proceso de descubrimiento de fármacos en Janssen: Diseño de mGlu2Nams

Susana Conde es actualmente “Principal Scientist” y Team Leader del departamento de Química Médica de Janssen en España. Su trayectoria investigadora ha sido brillante, siendo doctora en Química Orgánica por la Universidad de La Coruña en el año 2000 trabajando en síntesis de fosfono-aminoácidos como antagonistas competitivos del receptor NMDA. Tras su etapa predoctoral, realizó una estancia postdoctoral en el periodo 2000-2002 en el grupo del profesor Julius Rebek en el instituto Scripps en California donde trabajó en síntesis de péptido miméticos helicoidales. Entre 2002 y 2005, trabajó para la empresa Kemia Inc en California sobre varios programas de descubrimiento de fármacos en el área de HIV e inflamación. Finalmente, en 2005, la doctora Conde se unió a Janssen Pharmaceutica en España donde ha sido una persona esencial en la identificación y desarrollo de varios candidatos de los programas mGluR y PDE, relacionados con el tratamiento del Alzheimer. Es coautora de unas 40 contribuciones científicas entre artículos y patentes. La conferencia de la doctora Conde puede ser de gran interés no solo para el personal del departamento, por la relevancia científica de sus trabajos, sino también para los alumnos de grado de últimos cursos que podrán adquirir una visión de cómo es la investigación en el mundo de la empresa farmacéutica. Se programará la conferencia a las 12:30 con el objeto de que los alumnos, a los que se avisarán, puedan asistir.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission

Previous studies have shown that injection of the mGlu5 receptor positive allosteric modulator (PAM) VU0360172 into either the thalamus or somatosensory cortex markedly reduces the frequency of spike-and-wave discharges (SWDs) in the WAG/Rij model of absence epilepsy. Here we have investigated the effects of VU0360172 on GABA transport in the thalamus and somatosensory cortex, as possible modes of action underlying the suppression of SWDs. Systemic VU0360172 injections increase GABA uptake in thalamic synaptosomes from epileptic WAG/Rij rats. Consistent with this observation, VU0360172 could also enhance thalamic GAT-1 protein expression, depending on the dosing regimen. This increase in GAT-1 expression was also observed in the thalamus from non-epileptic rats (presymptomatic WAG/Rij and Wistar) and appeared to occur selectively in neurons. The tonic GABAA receptor current present in ventrobasal thalamocortical neurons was significantly reduced by VU0360172 consistent with changes in GAT-1 and GABA uptake. The in vivo effects of VU0360172 (reduction in tonic GABA current and increase in GAT-1 expression) could be reproduced in vitro by treating thalamic slices with VU0360172 for at least 1 hour and appeared to be dependent on the activation of PLC. Thus, the effects of VU0360172 do not require an intact thalamocortical circuit. In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models

Schizophrenia: synthetic strategies and recent advances in drug design

YesSchizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.The Royal Society, The Academy of Medical Sciences, The Wellcome Trust, The Government Department of Business, Energy and Industrial Strategy and the British Heart Foundation, The University of Bradford

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia

FWN – Publicaties zonder aanstelling Universiteit Leide

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo­[1,2-<i>a</i>]­pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound <b>25a</b> for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure–activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead <b>25a</b> are described