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

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

Discovery of VU0409551/JNJ-46778212: An mGlu₅ Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

Herein, we report the structure–activity relationship of a novel series of (2­(phenoxymethyl)-6,7-dihydrooxazolo­[5,4-<i>c</i>]­pyridine-5­(4<i>H</i>)-yl­(aryl)­methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu₅) positive allosteric modulators (PAMs). On the basis of its robust <i>in vitro</i> potency and <i>in vivo</i> efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, <b>17a</b> (VU0409551/JNJ-46778212) was selected as a candidate for further development

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu₅) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu₅ PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu₅ as well as antagonist activity at mGlu₃. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered <b>12c</b> (VU0405372), a selective mGlu₅ PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis