Novel potent and selective inverse agonists at the GABAA a5 receptor sub-type

MEDI 257

A W Thomas, andrew.thomas@roche.com1, T M Ballard2, F Blasco2, T Buttelmann1, H Fischer2, M-C Hernandez2, F Knoflach2, H Knust2, R Moog2, H Stadler2, G Trube2, P Waldmeier2, and M Wooley2. (1) Pharmaceutical Research Basel, Discovery Chemistry, Hoffmann-La Roche, PRBD-CM, 092/6.56, Basel, Switzerland, (2) F. Hoffmann-La Roche, Switzerland
Extensive detailed pharmacological evidence exists in both rodents and humans suggesting non-selective inverse agonists at the benzodiazepine site of the GABAA receptor (BZR) enhance cognitive functions. However, non-selective inverse agonists induce anxiogenic and pro-convulsive effects. Through the greater understanding of the complex pharmacology of the GABA A receptor sub-types it is now strongly believed that the cognitive effects are mediated through inverse agonism of the GABA A alpha5 receptor sub-type which has been supported by recent results in the clinic. Within our research program we have identified several novel series' of potent and selective GABAA alpha5 receptor inverse agonists. The poster will describe the discovery of an imidazotriazolobenzodiazepine chemical class, by lead optimisation of an imidazopyrimidinobenzazepine lead series, and culminate in the full profile of key compounds.

 

Palliative Approaches to the Treatment of Alzheimer's Disease
1:30 PM-4:25 PM, Wednesday, August 22, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007