Time：13:30-14:30 Friday 17th Feb
Venue：A136, building 2
Presenter：
Dr. Yves P. Auberson
Executive Director
Novartis Institutes for BioMedical Research
Abstract：
With few exceptions, earlier attempts to develop AMPA/kainate antagonists resulted from an extensive SAR exploration of substituted quinoxalinediones. Several clinical development compounds were identified (e.g. YM-90K, MPQX, or AMP397), but none of them proved suitable for full development and so far, no competitive AMPA/kainate antagonist made it to the market. In contrast to the previous candidates, BGG492, an orally active AMPA/kainate antagonist, results from the optimization of quinazolinedione sulfonamides, which have a similar SAR but improved overall properties.
BGG492 shows anticonvulsant activity in several animal models of epilepsy, including electroshock and chemically-induced seizures in rodents, WAG/Rij rats (a genetic model of absence epilepsy), the rat amygdala kindling model (indicating a potential anti-epileptogenic effect), and in fully kindled rats (a model of therapy-resistant partial seizures in human). It is well understood that properties required for high affinity at AMPA receptors are contrary to those required for oral bioavailability. As a compromise, BGG492 has moderate binding affinity for rat and human AMPA receptors (IC50 = 0.19 and 0.2 M), but >100-fold selectivity with regards to the glycine-binding site of NMDA receptors and no significant affinity in a 150-target safety panel. BGG492 is only metabolized to a limited extent, and does not inhibit CYP450 enzymes. Its very favorable safety profile is evidence by a lack of cardiovascular, phototoxic or teratogenic potential, as well as by results of in vivo toxicology studies in rats, dogs and monkeys, where only minor and reversible effects were observed. Dose-limiting adverse effects were related to the classical signs of exaggerated pharmacology for AMPA/kainate receptor antagonism, mostly ataxia and decreased locomotor activity. BGG492 is currently in clinical evaluation in epileptic, as well as tinnitus and migraine patients.
Brief Introduction of Prof. Yves P. Auberson
Yves Auberson received his Diploma in Chemical Engineering in 1986, and completed a Ph.D. Thesis in 1990 on total asymmetric synthesis of sugar derivatives with Professor Pierre Vogel at the Swiss Federal Institute of Technology in Lausanne, Switzerland. He went on to a post-doctoral training at Affymax in Palo Alto, USA, working on catalytic antibodies with Professor Peter Schulz, and then joined CIBA (now Novartis) in 1992. His major contributions relate to the discovery and development of the AMPA receptor antagonists AMP397 (Becampanel) and BGG492 (Selurampanel) for the treatment of epilepsy, AFQ056, an mGluR5 antagonist in Ph II clinical trials, as well as 123I-BZM055 and 11C-ABP688, two PET tracers in clinical use. After leading drug discovery programs for the treatment of psychiatric and neurodegenerative diseases, as well as for biomarker and imaging tracer discovery, he became Head of Chemistry for Neurodegeneration in 2002, and Global Head of Chemistry for Neuroscience and PET Imaging in 2005.
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